CLOCK

Summary

CLOCK (clock circadian regulator, HGNC:2082) is a protein-coding gene on chromosome 4q12, encoding Circadian locomoter output cycles protein kaput (O15516). Transcriptional activator which forms a core component of the circadian clock.

The protein encoded by this gene plays a central role in the regulation of circadian rhythms. The protein encodes a transcription factor of the basic helix-loop-helix (bHLH) family and contains DNA binding histone acetyltransferase activity. The encoded protein forms a heterodimer with ARNTL (BMAL1) that binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Polymorphisms in this gene may be associated with behavioral changes in certain populations and with obesity and metabolic syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 9575 — RefSeq curated summary.

At a glance

• GWAS associations: 22
• Clinical variants (ClinVar): 107 total — 1 pathogenic
• Transcription factor: yes — 72 downstream targets (CollecTRI)
• MANE Select transcript: NM_004898

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2082
Approved symbol	CLOCK
Name	clock circadian regulator
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0334, KAT13D, bHLHe8
Ensembl gene	ENSG00000134852
Ensembl biotype	protein_coding
OMIM	601851
Entrez	9575

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 15 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000309964, ENST00000381322, ENST00000435527, ENST00000479384, ENST00000506747, ENST00000506923, ENST00000508049, ENST00000509151, ENST00000511124, ENST00000513033, ENST00000513440, ENST00000882369, ENST00000882370, ENST00000882371, ENST00000882372, ENST00000882373, ENST00000882374, ENST00000926584, ENST00000926585, ENST00000926586, ENST00000962774, ENST00000962775

RefSeq mRNA: 2 — MANE Select: NM_004898 NM_001267843, NM_004898

CCDS: CCDS3500

Canonical transcript exons

ENST00000513440 — 23 exons

Exon	Start	End
ENSE00000916888	55453054	55453129
ENSE00000916889	55450091	55450232
ENSE00000916890	55449396	55449496
ENSE00000916895	55438282	55438537
ENSE00000916896	55427903	55435594
ENSE00001001877	55489374	55489465
ENSE00001001878	55509912	55510065
ENSE00001188022	55546782	55546909
ENSE00001792270	55453677	55453824
ENSE00003488260	55458892	55459010
ENSE00003492318	55442432	55442634
ENSE00003503398	55444633	55444785
ENSE00003563367	55463685	55463805
ENSE00003578495	55459148	55459261
ENSE00003598183	55443687	55443896
ENSE00003625345	55478815	55478963
ENSE00003632457	55456218	55456300
ENSE00003649117	55482739	55482828
ENSE00003649224	55479640	55479699
ENSE00003657910	55455897	55456003
ENSE00003674623	55448779	55448868
ENSE00003677930	55470717	55470806
ENSE00003685638	55475963	55476054

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 97.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.6737 / max 199.4382, expressed in 1674 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52165	1.5689	1033
52164	1.4358	889
52163	1.3253	836
52166	0.8415	562
52167	0.5022	274

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.83	gold quality
oocyte	CL:0000023	97.00	gold quality
germinal epithelium of ovary	UBERON:0001304	94.22	gold quality
caput epididymis	UBERON:0004358	94.16	gold quality
cauda epididymis	UBERON:0004360	93.89	gold quality
pigmented layer of retina	UBERON:0001782	93.81	gold quality
retina	UBERON:0000966	93.79	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.65	gold quality
tibia	UBERON:0000979	93.21	gold quality
tibialis anterior	UBERON:0001385	93.21	gold quality
gingival epithelium	UBERON:0001949	93.09	gold quality
gingiva	UBERON:0001828	93.08	gold quality
lower lobe of lung	UBERON:0008949	93.07	gold quality
biceps brachii	UBERON:0001507	92.96	gold quality
heart right ventricle	UBERON:0002080	92.92	gold quality
corpus epididymis	UBERON:0004359	92.70	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.50	gold quality
jejunal mucosa	UBERON:0000399	92.21	gold quality
mammalian vulva	UBERON:0000997	91.85	gold quality
seminal vesicle	UBERON:0000998	91.76	gold quality
oral cavity	UBERON:0000167	91.74	gold quality
cerebellar vermis	UBERON:0004720	91.69	gold quality
parietal pleura	UBERON:0002400	91.56	gold quality
urethra	UBERON:0000057	91.53	gold quality
jejunum	UBERON:0002115	91.50	gold quality
deltoid	UBERON:0001476	91.47	silver quality
esophagus squamous epithelium	UBERON:0006920	91.37	gold quality
calcaneal tendon	UBERON:0003701	91.22	gold quality
left ventricle myocardium	UBERON:0006566	91.17	gold quality
sperm	CL:0000019	91.16	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.45

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

72 targets.

Target	Regulation
ABCB1
ACOX1	Unknown
ATF4	Activation
ATF5	Repression
ATG14
BHLHE40	Activation
BHLHE41	Activation
BMAL1	Repression
CACNB2
CCK
CIART
CLOCK
CREBBP
CRY1	Activation
CRY2	Activation
CYP8B1	Unknown
DBP	Unknown
DEFB1	Unknown
DELEC1	Activation
DLST
DPYD	Activation
DUSP1
EP300	Unknown
F3
FKBP5	Activation
GYS2	Activation
ICAM1
INS
JUN
KAT5	Unknown

JASPAR motifs

Motif	Name	Family
MA0819.1	CLOCK	PAS domain factors
MA0819.2	CLOCK	PAS domain factors
MA0819.3	CLOCK	PAS domain factors

JASPAR matrix evidence (PMIDs): PMID:24591654

Upstream regulators (CollecTRI, top): BHLHE40, BHLHE41, BMAL1, CLOCK, ID2, KAT2B, MTA1, MYC, NR0B2, NR1D1, PASD1, RAI1

miRNA regulators (miRDB)

539 targeting CLOCK, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012

Literature-anchored findings (GeneRIF, showing 40)

• essential regulator of circadian rhythms (PMID:10198158)
• BMAL1 and CLOCK have roles in circadian system control (PMID:12897057)
• a role for the CLOCK gene polymorphism in the regulation of long-term illness recurrence in bipolar disorder (PMID:14582141)
• CLOCK was cloned & sequenced and its circadian expression studied. (PMID:14750904)
• Findings suggest the significance of the association of the 3111C/C allele of hClock with evening preference in a Japanese population sample. (PMID:15578592)
• RNA interference against beta-TRCP greatly decreases Clock-dependent gene expression in tissue culture cells, indicating that beta-TRCP controls endogenous Per1 activity and the circadian clock by directly targeting Per1 for degradation (PMID:15917222)
• Findings may suggest that CLOCK genotype influences the time course of insomnia during antidepressant treatment. (PMID:15952199)
• Single Nucleotide Polymorphism in the 3’-untranslated region of clock gene is associated with Sleep Disorders (PMID:16024980)
• Single nucleotide polymorphism is not associated with narcolepsy. (PMID:16125818)
• a molecular genetic screen in mammalian cells to identify mutants of the circadian transcriptional activators CLOCK and BMAL1. (PMID:16474406)
• The results of this study suggests that the T3111C polymorphism of the CLOCK gene is associated with schizophrenia. (PMID:17116390)
• compared to T/T homozygotes, bipolar depressed carriers of the C allele had a similar degree of severity of depression, but showed higher activity levels in the evening, a delayed sleep onset and a reduced amount of sleep during the night (PMID:17221848)
• These results show that there is no association between either polymorphism T3111C or T257G in the Clock gene with diurnal preference or delayed sleep phase syndrome (DSPS). (PMID:17364575)
• CLOCK 3111 T/C SNP was associated with activity levels in the second part of the day, neuropsychological performance and BOLD fMRI correlates (interaction of genotype and moral valence of the stimuli). (PMID:17428266)
• The difference between the mean value for the lowest expression individual (DeltaCT 8.8) and the highest expression individual (DeltaCT 3.7) revealed an approximately 34-fold difference in relative clock gene expression levels. (PMID:17469042)
• polymorphism of the CLOCK gene confers a predisposition to a lifetime lower body weight in patients with anorexia nervosa and bulimia nervosa (PMID:17516548)
• Our study suggests a potential role of the CLOCK polymorphisms and their haplotypes in susceptibility to nonalcoholic fatty liver disease and disease severity. (PMID:17696255)
• Allelic variants interaction of CLOCK gene and GNB3 subunit gene with diurnal preference. (PMID:17701674)
• peripheral clock in vascular endothelial cells regulates TM gene expression and that the oscillation of TM expression may contribute to the circadian variation of cardiovascular events (PMID:17848551)
• This is the first study suggesting that a polymorphism of a gene within the circadian “clock” mechanism is a direct or linked contributing factor in adult ADHD (PMID:17948273)
• CLOCK/BMAL1-mediated activation of PER1 by AP1 and E-Box elements is distinct from peripheral transcriptional modulation via cAMP-induced CREB and C/EBP. (PMID:17994337)
• the Clock gene CGC haplotype may be protective for the development of obesity and support the hypothesis that genetic variation in the Clock gene may play a role in the development of the metabolic syndrome, type 2 diabetes and cardiovascular disease. (PMID:18071340)
• A multi-locus interaction between rs6442925 in the 5’ upstream of BHLHB2, rs1534891 in CSNK1E, and rs534654 near the 3’ end of the CLOCK gene, however, is significantly associated with bipolar disorder (PMID:18228528)
• study does not support the hypothesis that the T3111C CLOCK polymorphism is associated with cluster headache (PMID:18283403)
• Present findings show for the first time that the 3111T/C SNP of the CLOCK gene is not associated to human obesity and/or BED, but it seems to predispose obese individuals to a higher BMI. (PMID:18314271)
• No relationship between hCLOCK T3111C polymorphism and endometriosis, nor any effect of the polymorphism on the relationship of shift work to endometriosis. (PMID:18379422)
• DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock CLOCK/BMAL1 (PMID:18411297)
• Evidence linking circadian rhythms, the Clock gene, and bipolar disorder is discussed, along with the possible biology that underlies this connection. Review. (PMID:18419323)
• The regulators of clock-controlled transcription PER2, CRY1 and CRY2 differ in their capacity to interact with each single component of the BMAL1-CLOCK heterodimer and, in the case of BMAL1, also in their interaction sites. (PMID:18430226)
• HAT gene expression is required for cisplatin resistance and Clock and Tip60 regulate not only transcription, but also DNA repair, through periodic histone acetylation (PMID:18458078)
• Putative role of the CLOCK polymorphism and related haplotypes in susceptibility to obesity. (PMID:18541547)
• The transcription of human nocturnin gene displayed circadian oscillations in Huh7 cells (a human hepatoma cell line) and was regulated by CLOCK/BMAL1 heterodimer via the E-box of nocturnin promoter. (PMID:18587630)
• Impairment of the circadian clock protein appears to be closely associated with the pathophysiology of type 2 diabetes in humans. (PMID:18974966)
• Data show that there are not significant association between CLOCK gene and pathophysiology of Japanese schizophrenia, bipolar disorder and major depressive disorder. (PMID:19224106)
• expression of CLOCK in breast cancer is associated significantly with 3-year survival (PMID:19296127)
• Results indicate that CLOCK genotype may be a predictor of fluvoxamine treatment response in Japanese major depressive disorder. (PMID:19347611)
• PER2 is inhibited by BMAL2-CLOCK, which reemphasizes its negative role and a positive role of BMAL2 in circadian transcription (PMID:19605937)
• Evidence suggests metabolic processes feed back into the circadian clock, affecting clock and per2 gene expression and timing of behaviour. (PMID:19714310)
• CLOCK polymorphisms interact with fatty acids to modulate metabolic syndrome X traits. (PMID:19846548)
• A novel association of genetic variation at CLOCK with total energy intake, which was particularly relevant for single nucleotide polymorphism rs3749474. (PMID:19888304)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	clockb	ENSDARG00000003631
danio_rerio	clocka	ENSDARG00000011703
mus_musculus	Clock	ENSMUSG00000029238
rattus_norvegicus	Clock	ENSRNOG00000002175
drosophila_melanogaster	Met	FBGN0002723
drosophila_melanogaster	gce	FBGN0261703
drosophila_melanogaster	tgo	FBGN0264075
caenorhabditis_elegans	aha-1	WBGENE00000095

Paralogs (6): BMAL2 (ENSG00000029153), BMAL1 (ENSG00000133794), ARNT (ENSG00000143437), PASD1 (ENSG00000166049), NPAS2 (ENSG00000170485), ARNT2 (ENSG00000172379)

Protein

Protein identifiers

Circadian locomoter output cycles protein kaput — O15516 (reviewed: O15516)

Alternative names: Class E basic helix-loop-helix protein 8

All UniProt accessions (2): C9JK03, O15516

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots ‘circa’ (about) and ‘diem’ (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for ’timegivers’). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5’-CACGTG-3’) within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. Regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. Plays an important role in the homeostatic regulation of sleep. The CLOCK-BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The CLOCK-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5’-CACGTGA-3’, which contains a flanking adenine nucleotide at the 3-prime end of the canonical 6-nucleotide E-box sequence. CLOCK specifically binds to the half-site 5’-CAC-3’, while BMAL1 binds to the half-site 5’-GTGA-3’. The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5’-AACGTGA-3’ and 5’-CATGTGA-3’. CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner BMAL1. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region. The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis. Drives the circadian rhythm of blood pressure through transcriptional activation of ATP1B1.

Subunit / interactions. Component of the circadian clock oscillator which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Interacts with KMT2A; in a circadian manner. Forms a heterodimer with BMAL1. The CLOCK-BMAL1 heterodimer is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and for phosphorylation of both CLOCK and BMAL1. Interacts with NR3C1 in a ligand-dependent fashion. Interacts with ESR1 and estrogen stimulates this interaction. Interacts with the complex p35/CDK5. Interacts with RELA/p65. Interacts with KAT2B, CREBBP, EP300. Interacts with ID1 and ID3. Interacts with ID2. Interacts with MTA1. Interacts with OGA. Interacts with SIRT1. Interacts with CIPC. Interacts with EZH2. Interacts with EIF4E, PIWIL1 and DDX4. Interacts with PER2 and CRY1 and the interaction with PER and CRY proteins requires translocation to the nucleus. Interacts with PER1 and CRY2. Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits transcription activation. Interaction of the CLOCK-BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA. The CLOCK-BMAL1 heterodimer interacts with GSK3B. Interacts with KDM5A. Interacts with MYBBP1A. Interacts with THRAP3. Interacts with MED1; this interaction requires the presence of THRAP3. Interacts with NCOA2. The CLOCK-BMAL1 heterodimer interacts with PASD1. Interacts with ASS1 and IMPDH2; in a circadian manner. Interacts with NDUFA9. Interacts with PIWIL2 (via PIWI domain). Interacts with HNF4A.

Subcellular location. Nucleus. Cytoplasm. Cytosol.

Tissue specificity. Hair follicles (at protein level). Expressed in all tissues examined including spleen, thymus, prostate, testis, ovary, small intestine, colon, leukocytes, heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Highest levels in testis and skeletal muscle. Low levels in thymus, lung and liver. Expressed in all brain regions with highest levels in cerebellum. Highly expressed in the suprachiasmatic nucleus (SCN).

Post-translational modifications. Ubiquitinated, leading to its proteasomal degradation. O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated transcriptional activation of PER1/2/3 and CRY1/2. Phosphorylation is dependent on the CLOCK-BMAL1 heterodimer formation. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver. May be phosphorylated by CSNK1D and CKSN1E. Sumoylation enhances its transcriptional activity and interaction with ESR1, resulting in up-regulation of ESR1 activity. Estrogen stimulates sumoylation. Desumoylation by SENP1 negatively regulates its transcriptional activity. Sumoylation stimulates cell proliferation and increases the proportion of S phase cells in breast cancer cell lines. Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.

Activity regulation. There is conflicting data about the effect of NAD cofactors on activity. PubMed:11441146 suggests that the redox state of the cell can modulate the transcriptional activity of the CLOCK-BMAL1 heterodimer; NADH and NADPH enhance the DNA-binding activity of the heterodimer. PubMed:23229515 reports that NADH and NADPH have no significant effect on DNA-binding activity of the CLOCK-BMAL1 heterodimer.

Miscellaneous. CLOCK-BMAL1 double mutations within the PAS domains result in synergistic desensitization to high levels of CRY on repression of CLOCK-BMAL1 transcriptional activity of PER1 and disrupt circadian rhythmicity.

RefSeq proteins (2): NP_001254772, NP_004889* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR001067	Nuc_translocat	Family
IPR001610	PAC	Repeat
IPR011598	bHLH_dom	Domain
IPR013767	PAS_fold	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR047230	CLOCK-like	Family

Pfam: PF00010, PF00989, PF14598

Enzyme classification (BRENDA):

• EC 2.3.1.48 — histone acetyltransferase (BRENDA: 41 organisms, 681 substrates, 1134 inhibitors, 140 Km, 96 kcat entries)

Substrate kinetics (BRENDA)

27 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-COA	0.0002–0.046	51
HISTONE H3	0.007–2.09	23
HISTONE H4	—	11
HISTONE H4 PEPTIDE	0.0208–0.197	7
HISTONE	0.075–1.4	6
HISTONE H3 TAIL PEPTIDE	0.044–0.112	4
PICCOLONUA4 PEPTIDE	0.135–0.372	4
3-AZIDOPROPIONYL-COA	0.0002–0.0086	3
4-PENTYNOYL-COA	0.0009–0.0859	3
SPERMIDINE	0.18–0.27	3
5-HEXYNOYL-COA	0.0006–0.0117	2
6-HEPTYNOYL-COA	0.0003–0.0237	2
HISTONE H3-PEPTIDE	0.05–0.49	2
PROTEIN P53	1.28–4.63	2
3-AZIDOPROPANOYL-COA	0.0103	1

Catalyzed reactions (Rhea), 1 shown:

• L-lysyl-[protein] + acetyl-CoA = N(6)-acetyl-L-lysyl-[protein] + CoA + H(+) (RHEA:45948)

UniProt features (64 total): mutagenesis site 12, helix 9, region of interest 8, modified residue 7, strand 6, compositionally biased region 5, domain 4, site 4, sequence variant 4, cross-link 2, chain 1, short sequence motif 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6QPJ	X-RAY DIFFRACTION	2.31
4H10	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15516-F1	61.90	0.33

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (4): 39 (interaction with e-box dna); 43 (interaction with e-box dna); 47 (interaction with e-box dna); 84 (important for interaction with bmal1)

Post-translational modifications (9): 38, 42, 408, 427, 431, 451, 461, 67, 842

Mutagenesis-validated functional residues (12):

Position	Phenotype
38	phosphomimetic mutant with no effect on dna binding or clock-bmal1 transcriptional activity.
42	phosphomimetic mutant with no effect on dna binding or clock-bmal1 transcriptional activity.
50	no effect on bmal1 binding.
84	impaired bmal1 binding.
116	3-fold increase in per1 reporter activity by clock-bmal1. some reduction of cry1 inhibition of clock-bmal1 transcription
332	3-fold increase in per1 reporter activity by clock-bmal1. some reduction of cry1 inhibition of clock-bmal1 transcription
360	3-fold increase in per1 reporter activity by clock-bmal1. some reduction of cry1 inhibition of clock-bmal1 transcription
367	3-fold increase in per1 reporter activity by clock-bmal1. some reduction of cry1 inhibition of clock-bmal1 transcription
451	significant loss in phosphorylation.
461	significant loss in phosphorylation.
601	3-fold increase in per1 reporter activity by clock-bmal1. some reduction of cry1 inhibition of clock-bmal1 transcription
840	3-fold increase in per1 reporter activity by clock-bmal1. some reduction of cry1 inhibition of clock-bmal1 transcription

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1368108	BMAL1:CLOCK,NPAS2 activates circadian expression
R-HSA-1989781	PPARA activates gene expression
R-HSA-3214847	HATs acetylate histones
R-HSA-9707616	Heme signaling
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-9931512	Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters
R-HSA-9931521	The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex
R-HSA-9931529	Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK

MSigDB gene sets: 565 (showing top): GOBP_CIRCADIAN_RHYTHM, MORF_RAGE, CREL_01, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT, MORF_FLT1, MORF_MSH3, GOBP_INFLAMMATORY_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_PHOTOPERIODISM, GOBP_INSULIN_SECRETION, MORF_ATRX, GOBP_CELL_CYCLE_PHASE_TRANSITION

GO Biological Process (28): DNA damage checkpoint signaling (GO:0000077), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), protein acetylation (GO:0006473), signal transduction (GO:0007165), spermatogenesis (GO:0007283), circadian rhythm (GO:0007623), photoperiodism (GO:0009648), gene expression (GO:0010467), circadian regulation of gene expression (GO:0032922), regulation of hair cycle (GO:0042634), regulation of circadian rhythm (GO:0042752), positive regulation of circadian rhythm (GO:0042753), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of inflammatory response (GO:0050729), regulation of insulin secretion (GO:0050796), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), response to redox state (GO:0051775), cellular response to ionizing radiation (GO:0071479), regulation of type B pancreatic cell development (GO:2000074), negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway (GO:2000323), chromatin remodeling (GO:0006338), DNA damage response (GO:0006974), regulation of gene expression (GO:0010468), positive regulation of transcription by RNA polymerase II (GO:0045944), rhythmic process (GO:0048511)

GO Molecular Function (15): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), histone acetyltransferase activity (GO:0004402), chromatin DNA binding (GO:0031490), sequence-specific DNA binding (GO:0043565), protein dimerization activity (GO:0046983), E-box binding (GO:0070888), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), protein-lysine-acetyltransferase activity (GO:0061733)

GO Cellular Component (9): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytosol (GO:0005829), chromatoid body (GO:0033391), CLOCK-BMAL transcription complex (GO:1990513), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Circadian clock	6
Regulation of lipid metabolism by PPARalpha	1
Chromatin modifying enzymes	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
cellular anatomical structure	4
DNA-templated transcription	3
circadian rhythm	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of gene expression	2
DNA binding	2
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
protein acylation	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
developmental process involved in reproduction	1
male gamete generation	1
rhythmic process	1
response to light stimulus	1
macromolecule biosynthetic process	1
hair cycle	1
regulation of multicellular organismal process	1
regulation of biological process	1
regulation of circadian rhythm	1
positive regulation of biological process	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
insulin secretion	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
response to stimulus	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

1704 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLOCK	CRY1	Q16526	996
CLOCK	SIRT1	Q96EB6	995
CLOCK	BMAL1	O00327	991
CLOCK	CRY2	Q49AN0	984
CLOCK	EP300	Q09472	983
CLOCK	KDM5A	P29375	983
CLOCK	CREBBP	Q92793	965
CLOCK	BMAL2	Q8WYA1	962
CLOCK	NR1D1	P20393	951
CLOCK	TIMELESS	Q9UNS1	949
CLOCK	NPAS2	Q99743	943
CLOCK	BHLHE41	Q9C0J9	915
CLOCK	CSNK1E	P49674	887
CLOCK	NR1D2	Q14995	886
CLOCK	KDM1A	O60341	885

IntAct

90 interactions, top by confidence:

A	B	Type	Score
CLOCK	BMAL1	psi-mi:“MI:0915”(physical association)	0.880
BMAL1	CLOCK	psi-mi:“MI:0914”(association)	0.880
CLOCK	BMAL1	psi-mi:“MI:0914”(association)	0.880
BMAL1	CLOCK	psi-mi:“MI:0915”(physical association)	0.880
BMAL1	CLOCK	psi-mi:“MI:0914”(association)	0.720
BMAL1	CLOCK	psi-mi:“MI:0915”(physical association)	0.720
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.670
CLOCK	BMAL2	psi-mi:“MI:0915”(physical association)	0.670
Cry1	CLOCK	psi-mi:“MI:0915”(physical association)	0.550
BMAL2	CLOCK	psi-mi:“MI:0915”(physical association)	0.550
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.550
TEKT4	CLOCK	psi-mi:“MI:0914”(association)	0.530
CIPC	CLOCK	psi-mi:“MI:0914”(association)	0.530
CRY1	CLOCK	psi-mi:“MI:0914”(association)	0.530
POC1A	TXNDC9	psi-mi:“MI:0914”(association)	0.480

BioGRID (132): CLOCK (Two-hybrid), CLOCK (Two-hybrid), CRY1 (Two-hybrid), CRY2 (Two-hybrid), DEC1 (Two-hybrid), BHLHE41 (Two-hybrid), NPAS2 (Two-hybrid), PPP2R5D (Two-hybrid), PPP2R5E (Two-hybrid), CSNK2B (Two-hybrid), PPP2R1B (Two-hybrid), NR1D2 (Two-hybrid), PER2 (Two-hybrid), PPP1CA (Two-hybrid), PPP1CB (Two-hybrid)

ESM2 similar proteins: A2BID7, B1AWL2, B4F6U4, H2L008, O08785, O15164, O15516, P57071, P70121, Q08BR4, Q0P5J0, Q0VCJ6, Q2TAL8, Q3UA37, Q3UTQ7, Q502P7, Q56R14, Q58NQ5, Q5FWL0, Q5NBY9, Q5RAK8, Q5RAX9, Q5RGA4, Q5XJV7, Q62415, Q64127, Q6DJT9, Q6E2N3, Q6INA9, Q6YGZ4, Q7Z3K3, Q8BZH4, Q8K0L9, Q8N187, Q8N9N5, Q8QG78, Q8QGQ6, Q8R515, Q8VBU8, Q91YB0

Diamond homologs: A0MLS5, A6NFD8, O00327, O02219, O02748, O08785, O15516, O15945, O61734, O88529, P27540, P41739, P53762, P79832, P90953, P97460, Q2NL18, Q2VPD4, Q5R4T2, Q5RAK8, Q5ZQU2, Q61324, Q6YGZ4, Q6YGZ5, Q78E60, Q7TS99, Q8BGD7, Q8IUM7, Q8QGQ6, Q8QGQ7, Q8WYA1, Q91YA8, Q91YA9, Q91YB0, Q91YB2, Q99743, Q9BE97, Q9DBX7, Q9DG12, Q9EPW1

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
CDK5	up-regulates	CLOCK	phosphorylation
CLOCK	“down-regulates activity”	MAGEL2	binding
CLOCK	“down-regulates quantity by repression”	NR3C1	“transcriptional regulation”
CLOCK	“form complex”	BMAL1/NPAS2	binding
GSK3B	“down-regulates quantity by destabilization”	CLOCK	phosphorylation
CLOCK	“up-regulates quantity by expression”	NR0B2	“transcriptional regulation”
RAI1	“up-regulates quantity by expression”	CLOCK	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	CRY1	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	CRY2	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	PER1	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	PER2	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	PER3	“transcriptional regulation”
CLOCK	“form complex”	CLOCK/BMAL1	binding
CLOCK	“form complex”	CLOCK/BMAL2	binding
CLOCK	“up-regulates quantity by expression”	DPYD	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 58 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
endocytic recycling	5	25.7×	2e-04
circadian regulation of gene expression	5	22.5×	2e-04
protein transport	9	7.6×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

107 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	77
Likely benign	6
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1703552	GRCh37/hg19 4q12(chr4:53688710-56491447)	Pathogenic

SpliceAI

3991 predictions. Top by Δscore:

Variant	Effect	Δscore
4:55438277:ATTAC:A	donor_loss	1.0000
4:55438278:TTAC:T	donor_loss	1.0000
4:55438279:TAC:T	donor_loss	1.0000
4:55438280:A:C	donor_loss	1.0000
4:55442435:ATCTG:A	donor_gain	1.0000
4:55442436:T:C	donor_gain	1.0000
4:55443839:C:CT	acceptor_gain	1.0000
4:55443839:C:T	acceptor_gain	1.0000
4:55443894:CAT:C	acceptor_gain	1.0000
4:55443897:C:CC	acceptor_gain	1.0000
4:55443898:T:C	acceptor_gain	1.0000
4:55443899:T:C	acceptor_gain	1.0000
4:55444629:TTA:T	donor_loss	1.0000
4:55444630:TACC:T	donor_loss	1.0000
4:55444631:AC:A	donor_loss	1.0000
4:55444632:CCT:C	donor_loss	1.0000
4:55444794:CCATG:C	acceptor_gain	1.0000
4:55444795:CA:C	acceptor_gain	1.0000
4:55444796:A:AC	acceptor_gain	1.0000
4:55444796:A:C	acceptor_gain	1.0000
4:55449391:CTTA:C	donor_loss	1.0000
4:55449393:TA:T	donor_loss	1.0000
4:55449394:A:AG	donor_loss	1.0000
4:55449395:CCTGA:C	donor_gain	1.0000
4:55449492:TGTTG:T	acceptor_gain	1.0000
4:55449493:GTTG:G	acceptor_gain	1.0000
4:55449494:TTG:T	acceptor_gain	1.0000
4:55449495:TG:T	acceptor_gain	1.0000
4:55449496:GC:G	acceptor_loss	1.0000
4:55449497:C:CA	acceptor_loss	1.0000

AlphaMissense

5597 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:55444661:A:G	L555P	1.000
4:55444682:A:G	L548P	1.000
4:55444691:T:G	Q545P	1.000
4:55444727:C:G	R533P	1.000
4:55444736:A:G	L530S	1.000
4:55453694:A:C	C371W	1.000
4:55453695:C:T	C371Y	1.000
4:55453696:A:G	C371R	1.000
4:55453701:A:T	I369N	1.000
4:55453703:A:C	F368L	1.000
4:55453703:A:T	F368L	1.000
4:55453704:A:G	F368S	1.000
4:55453705:A:G	F368L	1.000
4:55453710:G:T	P366Q	1.000
4:55453711:G:A	P366S	1.000
4:55453721:C:A	W362C	1.000
4:55453721:C:G	W362C	1.000
4:55453722:C:G	W362S	1.000
4:55453723:A:G	W362R	1.000
4:55453723:A:T	W362R	1.000
4:55453732:A:C	Y359D	1.000
4:55453737:A:T	I357N	1.000
4:55453749:G:A	T353I	1.000
4:55453755:A:G	L351P	1.000
4:55453755:A:T	L351H	1.000
4:55453759:A:G	W350R	1.000
4:55453759:A:T	W350R	1.000
4:55453765:A:G	W348R	1.000
4:55453765:A:T	W348R	1.000
4:55453775:C:A	K344N	1.000

dbSNP variants (sampled 300 via entrez): RS1000057798 (4:55486337 G>A), RS1000070451 (4:55440593 C>A,G), RS1000071144 (4:55484065 A>G), RS1000088900 (4:55433483 G>C), RS1000121491 (4:55433152 T>C), RS1000128370 (4:55476816 G>A), RS10001323 (4:55532849 C>A,G), RS1000141496 (4:55524603 T>C), RS1000172448 (4:55539656 G>A,C), RS1000190331 (4:55462801 G>A), RS1000227283 (4:55547394 T>C,G), RS1000246312 (4:55500844 G>A,T), RS1000251264 (4:55468597 A>G), RS10002541 (4:55528844 T>C), RS1000330241 (4:55492432 T>C)

Disease associations

OMIM: gene MIM:601851 | disease phenotypes: MIM:172800

GenCC curated gene-disease

Mondo (1): piebaldism (MONDO:0008244)

Orphanet (1): Piebaldism (Orphanet:2884)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000273_2	Personality dimensions	2.000000e-06
GCST002647_23	Height	8.000000e-09
GCST005962_39	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-06
GCST010699_101	Brain morphology (min-P)	1.000000e-11
GCST010701_29	Cortical surface area (MOSTest)	2.000000e-31
GCST010702_108	Subcortical volume (MOSTest)	1.000000e-09
GCST010703_345	Brain morphology (MOSTest)	4.000000e-10
GCST010866_51	Coronary artery disease	5.000000e-08
GCST012227_1028	Hip circumference adjusted for BMI	7.000000e-10
GCST90002399_422	Neutrophil percentage of white cells	3.000000e-09
GCST90020024_701	A body shape index	7.000000e-12
GCST90020025_321	Waist-to-hip ratio adjusted for BMI	4.000000e-16
GCST90020025_322	Waist-to-hip ratio adjusted for BMI	2.000000e-25
GCST90020026_283	Hip index	7.000000e-16
GCST90020026_284	Hip index	2.000000e-08
GCST90020026_286	Hip index	2.000000e-16
GCST90020027_1896	Waist-hip index	6.000000e-16
GCST90020027_1897	Waist-hip index	2.000000e-26
GCST90020028_1927	Hip circumference adjusted for BMI	3.000000e-08
GCST90020028_1932	Hip circumference adjusted for BMI	9.000000e-16
GCST90020028_1933	Hip circumference adjusted for BMI	4.000000e-14
GCST90020029_697	Waist circumference adjusted for body mass index	5.000000e-11

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004365	personality trait
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004346	neuroimaging measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016116	Piebaldism	C16.320.290.040.600; C16.320.565.100.102.600; C16.320.850.080.600; C17.800.621.440.102.600; C17.800.827.080.600; C18.452.648.100.102.600

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1522113	Efficacy	3	salbutamol	Asthma
rs1801260	Toxicity	4	lithium	Bipolar Disorder

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1522113	CLOCK	3	0.00	1	salbutamol
rs1801260	CLOCK, TMEM165	4	-1.50	1	lithium
rs3736544	CLOCK, TMEM165		0.00	0
rs34897046	CLOCK		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 2.3.1.48 Histone acetyltransferases (HATs)

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation	3
epigallocatechin gallate	affects cotreatment, affects expression, affects reaction, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, decreases expression	2
Hydrogen Peroxide	affects cotreatment, affects expression, affects reaction	2
Particulate Matter	increases abundance, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases activity	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
pentanal	decreases expression	1
gallocatechol	affects cotreatment, affects expression, affects reaction	1
2-(4-(2-carboxyethyl)phenethylamino)-5’-N-ethylcarboxamidoadenosine	increases expression	1
epicatechin gallate	affects reaction, affects cotreatment, affects expression	1
di-n-butylphosphoric acid	affects expression	1
PCB 180	affects expression	1
jinfukang	decreases expression	1
KL001	decreases expression, decreases reaction, increases expression	1
Sunitinib	increases expression	1
Acrolein	increases abundance, affects cotreatment, increases expression	1
Vehicle Emissions	increases abundance, decreases expression	1
Benzo(a)pyrene	increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Clozapine	affects response to substance	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1NK	Abcam HeLa CLOCK KO 1	Cancer cell line	Female
CVCL_B1NL	Abcam HeLa CLOCK KO 2	Cancer cell line	Female
CVCL_B8DV	Abcam HCT 116 CLOCK KO	Cancer cell line	Male
CVCL_B8U7	Abcam MCF-7 CLOCK KO	Cancer cell line	Female
CVCL_B9G3	Abcam A-549 CLOCK KO	Cancer cell line	Male

Clinical trials (associated diseases)

5 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01377077	PHASE4	UNKNOWN	Punchgrafting Techniques for Vitiligo
NCT01640678	PHASE4	UNKNOWN	Autologous Cell Suspension Grafting Using ReCell in Vitiligo and Piebaldism Patients
NCT02458417	PHASE4	COMPLETED	Autologous Cell Suspension Grafting Using ReCell in Vitiligo and Piebaldism Patients
NCT02156427	PHASE3	COMPLETED	Evaluation of Non-cultured Epidermal Cellular Grafting vs Hyaluronic Acid for Repigmenting Vitiligo and Piebaldism
NCT04919993	Not specified	COMPLETED	CBT for Insomnia in Primary Brain Tumor Patients