PER1

Summary

PER1 (period circadian regulator 1, HGNC:8845) is a protein-coding gene on chromosome 17p13.1, encoding Period circadian protein homolog 1 (O15534). Transcriptional repressor which forms a core component of the circadian clock.

This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene may increase the risk of getting certain cancers. Alternative splicing has been observed in this gene; however, these variants have not been fully described.

Source: NCBI Gene 5187 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 242 total
• MANE Select transcript: NM_002616

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8845
Approved symbol	PER1
Name	period circadian regulator 1
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	RIGUI
Ensembl gene	ENSG00000179094
Ensembl biotype	protein_coding
OMIM	602260
Entrez	5187

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 14 protein_coding, 9 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000317276, ENST00000354903, ENST00000577253, ENST00000577424, ENST00000578089, ENST00000578223, ENST00000578950, ENST00000579065, ENST00000579098, ENST00000579203, ENST00000581082, ENST00000581395, ENST00000581703, ENST00000582719, ENST00000583559, ENST00000583677, ENST00000584202, ENST00000585095, ENST00000585284, ENST00000857860, ENST00000857861, ENST00000857862, ENST00000857863, ENST00000857864, ENST00000857865, ENST00000929275

RefSeq mRNA: 1 — MANE Select: NM_002616 NM_002616

CCDS: CCDS11131

Canonical transcript exons

ENST00000317276 — 23 exons

Exon	Start	End
ENSE00001236764	8146897	8147002
ENSE00001236791	8147250	8147381
ENSE00001236833	8148644	8148786
ENSE00001236837	8149259	8149310
ENSE00001236846	8149462	8149663
ENSE00001709942	8144751	8144993
ENSE00001801765	8143266	8143876
ENSE00002705737	8140472	8141340
ENSE00003465848	8147470	8147578
ENSE00003467640	8152337	8152404
ENSE00003534537	8149755	8149876
ENSE00003548421	8142649	8142835
ENSE00003565728	8149971	8150125
ENSE00003571655	8146594	8146765
ENSE00003576605	8147674	8147827
ENSE00003580480	8150432	8150845
ENSE00003592059	8141805	8141955
ENSE00003606050	8147997	8148103
ENSE00003606751	8146372	8146502
ENSE00003631592	8142269	8142458
ENSE00003632663	8145958	8146137
ENSE00003662410	8150219	8150317
ENSE00003669764	8148181	8148259

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.6427 / max 1497.0783, expressed in 1773 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164381	16.7701	1542
164378	15.3923	1671
164379	0.7919	424
164375	0.3197	84
164377	0.2979	138
164368	0.1912	80
164365	0.1606	59
208053	0.1478	52
164374	0.1431	54
164369	0.1081	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	99.53	gold quality
tibial nerve	UBERON:0001323	99.34	gold quality
skin of leg	UBERON:0001511	99.30	gold quality
skin of abdomen	UBERON:0001416	99.27	gold quality
right ovary	UBERON:0002118	99.26	gold quality
left ovary	UBERON:0002119	99.23	gold quality
popliteal artery	UBERON:0002250	99.19	gold quality
tibial artery	UBERON:0007610	99.19	gold quality
right lung	UBERON:0002167	99.18	gold quality
left uterine tube	UBERON:0001303	99.14	gold quality
adenohypophysis	UBERON:0002196	98.93	gold quality
left lobe of thyroid gland	UBERON:0001120	98.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.89	gold quality
right lobe of thyroid gland	UBERON:0001119	98.88	gold quality
aorta	UBERON:0000947	98.86	gold quality
ectocervix	UBERON:0012249	98.82	gold quality
sural nerve	UBERON:0015488	98.76	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.72	gold quality
omental fat pad	UBERON:0010414	98.71	gold quality
lower esophagus	UBERON:0013473	98.70	gold quality
upper lobe of left lung	UBERON:0008952	98.68	gold quality
gastrocnemius	UBERON:0001388	98.67	gold quality
peritoneum	UBERON:0002358	98.66	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.62	gold quality
ascending aorta	UBERON:0001496	98.61	gold quality
thoracic aorta	UBERON:0001515	98.57	gold quality
apex of heart	UBERON:0002098	98.50	gold quality
descending thoracic aorta	UBERON:0002345	98.47	gold quality
left coronary artery	UBERON:0001626	98.41	gold quality
pituitary gland	UBERON:0000007	98.33	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	5.04
E-MTAB-6386	no	6.44
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
BAX	Repression
BCL2	Activation
SLC5A1	Repression

Upstream regulators (CollecTRI, top): AHR, BHLHE40, BHLHE41, BMAL1, BMAL2, CLOCK, CREB1, CREM, DBP, EGR1, EGR2, FOS, ID2, MAFF, MITF, MYC, NFIL3, NPAS2, NR2F6, NR3C1, NR4A1, NR4A2, SALL1, SFPQ, SIRT1, SP1

miRNA regulators (miRDB)

70 targeting PER1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053

Literature-anchored findings (GeneRIF, showing 40)

• human Per1 (hPER1) reporter gene activity shows circadian rhythmicity in a human neuroblastoma, but not in a astrocytoma or a hepatoma cell line. (PMID:12916719)
• Circadian oscillations of Per1, Per2, and Per3 mRNA expression were observed in serum-stimulated normal human fibroblasts. (PMID:14712925)
• Circadian hPER1 degradation through a proteasomal pathway can be regulated through phosphorylation by CKI, but not by subcellular localization. The mRNA levels reached a maximum at 1 h & minimal levels at 12 h. (PMID:14750904)
• physical chemistry and three-dimensional structure of the protein transduction domain (PMID:15781181)
• disturbances in PER gene expression may result in disruption of the control of the normal circadian clock, thus benefiting the survival of cancer cells and promoting carcinogenesis (PMID:15790588)
• 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)
• Per1 provides an important link between the circadian system and the cell cycle system. (PMID:16678109)
• These results together suggested that RACK1 might act as a novel signal molecule to mediate or regulate the functions of PER1 through protein interaction. (PMID:16757810)
• This is the first reported association between a PER1 polymorphism and extreme diurnal preference (PMID:17051316)
• Haplotype analysis of clock gene variants with autistic disorder resulted in per1 having a single significant result for the markers rs2253820-rs885747. (PMID:17264841)
• We have examined the circadian expression of clock genes in human leukocytes and found that Per1 mRNA exhibits a robust circadian expression (PMID:17274950)
• clear circadian rhythm was shown for hPer1, hPer2, and hCry2 expression in CD34(+) cells and for hPer1 in the whole bone marrow, with maxima from early morning to midday. (PMID:17440215)
• Our data indicate that PER1 transcription is mainly uncoupled from promoter methylation but probably involves availability. (PMID:17592726)
• Photoreceptor layers obtained from Period1-luciferase transgenic rats express a robust circadian rhythm in bioluminescence, and demonstrate that mammalian photoreceptors contain a circadian pacemaker that can drive rhythmic melatonin synthesis. (PMID:17621597)
• Results revealed a disturbed transcription of Per1 during tumor progression, which might be the cause for disrupted daily oscillation of DPD in undifferentiated colon carcinoma cells. (PMID:17699798)
• direct interaction between RACK1 and PER1 (PMID:17718421)
• a role for both Per1 and Per2 in normal breast function and show for the first time that deregulation of the circadian clock may be an important factor in the development of familial breast cancer (PMID:17971899)
• 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)
• obstructive sleep apnoea syndrome caused disruptions of periodic expression of PER1(period homolog 1) mRNA in peripheral blood leukocytes. (PMID:18321934)
• The expression level of PER1 was decreased in hepatocellular carcinoma. (PMID:18444243)
• Involved in the inhibition of proliferation of MIA-PaCa2 pancreatic cancer cells by TNF-alpha. (PMID:18480551)
• Variations in circadian genes are associated with serum levels of androgens and IGF markers, particularly PER1 rs2585405:G>C(Ala962Pro). (PMID:18990770)
• There was no significant age-related phase difference in PER1 or PER2 rhythm with respect to sleep timing; however, PER3 expression pattern was altered in the older subjects. (PMID:19013183)
• data demonstrate a correlated decrease of Per1 and ER-beta in colorectal tumors, mediated probably by epigenetic mechanisms (PMID:19148895)
• expression of PER2 is significantly associated with lymph node metastasis and poor prognosis in breast cancer (PMID:19296127)
• PER1 acts as an anti-apoptotic factor in pancreatic cancer cells (PMID:19675098)
• Overexpression of Per1 in prostate cancer cells resulted in significant growth inhibition and apoptosis. Results support the emerging role of circadian genes as key players in malignant transformation. (PMID:19752089)
• Sleep-wake cycles have been shown to influence the rhythmic mRNA expression of clock genes in peripheral blood cells of healthy participants (PMID:19861640)
• We found that overnight expression of BMAL1, but not PER1, was reduced in Parkinson’s disease. Because our sampling span was limited to 12 h, we cannot rule out the possibility that PER1 is expressed differently during the unsampled part of the day. (PMID:19912323)
• A small population of rhythmic neurons in Per1-deficient suprachiasmatic nuclei explants is sufficient to control wheel-running activity. (PMID:19923301)
• The expression levels of Per1 in glioma cells were significantly different from the surrounding non-glioma cells. The difference in the expression rate of Per1 in high-grade (grade III and IV) and low-grade (grade 1 and II) gliomas was insignificant. (PMID:20481271)
• There were no significant differences in PER1 expression between patients with Alzheimer’s dementia, those with mild cognitive impairment, and controls. An increase in PER1 expression during the wake stage is observed for all three groups. (PMID:20541418)
• ID2 can interact with the canonical clock components CLOCK and BMAL1 and mediate inhibitory effects on mPer1 expression (PMID:20861012)
• Overexpression of the Bmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. (PMID:21380491)
• Lean individuals exhibited significant (P < 0.05) temporal changes of core clock (PER1, PER2, PER3, CRY2, BMAL1, and DBP) and metabolic (REVERBalpha, RIP140, and PGC1alpha) genes. (PMID:21411511)
• PER1 and PER3 may modulate apoptotic reactions to cisplatin in gingival cancer cells (PMID:21459569)
• treatment with isoprenaline or dexamethasone induces circadian expression of hPer1, hPer2, hPer3, and hBMAL1 (PMID:22217103)
• dose-specific glucocorticoid responses are specific, able to distinctly express a single gene,PER1; mapped PER1 response to a single GR binding site; overexpression of PER1 led to regulation of additional circadian rhythm genes suggesting hypersensitive expression of PER1 impacts circadian gene expression (PMID:22801371)
• A common polymorphism near PER1 is associated with the timing of human behavioral rhythms, and shows evidence of association with time of death. (PMID:23034908)
• Expression of the CLOCK, BMAL1, and PER1 circadian genes in human oral mucosa cells as dependent on CLOCK gene polymorphic variants. (PMID:23129285)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	per1b	ENSDARG00000012499
danio_rerio	per1a	ENSDARG00000056885
mus_musculus	Per1	ENSMUSG00000020893
rattus_norvegicus	Per1	ENSRNOG00000007387
drosophila_melanogaster	per	FBGN0003068
caenorhabditis_elegans		WBGENE00018572

Paralogs (2): PER3 (ENSG00000049246), PER2 (ENSG00000132326)

Protein

Protein identifiers

Period circadian protein homolog 1 — O15534 (reviewed: O15534)

Alternative names: Circadian clock protein PERIOD 1, Circadian pacemaker protein Rigui

All UniProt accessions (8): O15534, J3KRL7, J3KSL6, J3KTM2, J3QL46, J3QL55, J3QLQ5, J3QSH9

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor 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 circadian target genes expression at post-transcriptional levels, but may not be required for the repression at transcriptional level. Controls PER2 protein decay. Represses CRY2 preventing its repression on CLOCK/BMAL1 target genes such as FXYD5 and SCNN1A in kidney and PPARA in liver. Besides its involvement in the maintenance of the circadian clock, has an important function in the regulation of several processes. Participates in the repression of glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) by BMAL1:CLOCK. Plays a role in the modulation of the neuroinflammatory state via the regulation of inflammatory mediators release, such as CCL2 and IL6. In spinal astrocytes, negatively regulates the MAPK14/p38 and MAPK8/JNK MAPK cascades as well as the subsequent activation of NFkappaB. Coordinately regulates the expression of multiple genes that are involved in the regulation of renal sodium reabsorption. Can act as gene expression activator in a gene and tissue specific manner, in kidney enhances WNK1 and SLC12A3 expression in collaboration with CLOCK. Modulates hair follicle cycling. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1.

Subunit / interactions. Homodimer. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts directly with TIMELESS, PER2, PER3, CRY1 and CRY2. Interacts with BMAL1 and CLOCK. Interacts with GPRASP1. Interacts (phosphorylated) with BTRC and FBXW11; the interactions trigger proteasomal degradation. Interacts with NONO, WDR5 and SFPQ. Interacts with USP2. Interacts with HNF4A.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Widely expressed. Expressed in hair follicles (at protein level). Found in heart, brain, placenta, lung, liver, skeletal muscle, pancreas, kidney, spleen, thymus, prostate, testis, ovary and small intestine. Highest level in skeletal muscle.

Post-translational modifications. Phosphorylated on serine residues by CSNK1D, CSNK1E and probably also by CSNK1G2. Phosphorylation by CSNK1D or CSNK1E promotes nuclear location of PER proteins as well as ubiquitination and subsequent degradation. May be dephosphorylated by PP1. Ubiquitinated; requires phosphorylation by CSNK1E and interaction with BTRC and FBXW11. Deubiquitinated by USP2.

Induction. Serum-induced levels in fibroblasts show circadian oscillations. Maximum levels after 1 hour stimulation, minimum levels after 12 hours. Another peak is then observed after 20 hours. Protein levels show maximum levels at 6 hours, decrease to reach minimum levels at 20 hours, and increase again to reach a second peak after 26 hours. Levels then decrease slightly and then increase to maximum levels at 32 hours. Levels of phosphorylated form increase between 3 hours and 12 hours.

Isoforms (4)

UniProt ID	Names	Canonical?
O15534-1	Rigui 4.7	yes
O15534-2	Rigui 3.0
O15534-3	Rigui 6.6, Truncated
O15534-4	2

RefSeq proteins (1): NP_002607* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR013655	PAS_fold_3	Domain
IPR022728	Period_circadian-like_C	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR048814	Per1-3_PAS-A	Domain
IPR050760	Period_circadian_regulator	Family
IPR057310	PER1-3_bHLH	Domain

Pfam: PF08447, PF12114, PF21353, PF23170

UniProt features (57 total): compositionally biased region 14, region of interest 12, modified residue 9, sequence variant 6, short sequence motif 5, mutagenesis site 4, domain 3, splice variant 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15534-F1	53.59	0.17

Functional residue map

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

Post-translational modifications (9): 121, 122, 126, 661, 663, 704, 815, 979, 980

Mutagenesis-validated functional residues (4):

Position	Phenotype
121–126	strongly decreases interaction with btrc and fbxw11 and inhibits degradation promoted by csnk1e.
210–213	no effect on interaction with btrc and fbxw11.
714–726	no effect on interaction with btrc and fbxw11.
794–798	strongly decreases interaction with btrc and fbxw11.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-9931521	The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex
R-HSA-9931530	Phosphorylation and nuclear translocation of the CRY:PER:kinase complex
R-HSA-9932298	Degradation of CRY and PER proteins
R-HSA-9931512	Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters

MSigDB gene sets: 411 (showing top): GOBP_CIRCADIAN_RHYTHM, ATF_B, TGGTGCT_MIR29A_MIR29B_MIR29C, MODULE_52, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_PHOTOPERIODISM, ENK_UV_RESPONSE_KERATINOCYTE_UP, AMIT_EGF_RESPONSE_60_HELA, GCANCTGNY_MYOD_Q6, CMYB_01, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP

GO Biological Process (19): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of sodium ion transport (GO:0002028), chromatin remodeling (GO:0006338), circadian rhythm (GO:0007623), entrainment of circadian clock (GO:0009649), post-transcriptional regulation of gene expression (GO:0010608), circadian regulation of gene expression (GO:0032922), regulation of hair cycle (GO:0042634), regulation of circadian rhythm (GO:0042752), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), entrainment of circadian clock by photoperiod (GO:0043153), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of JNK cascade (GO:0046329), response to cAMP (GO:0051591), regulation of cytokine production involved in inflammatory response (GO:1900015), regulation of p38MAPK cascade (GO:1900744), negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway (GO:2000323), rhythmic process (GO:0048511)

GO Molecular Function (9): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), transcription corepressor binding (GO:0001222), kinase binding (GO:0019900), chromatin DNA binding (GO:0031490), ubiquitin protein ligase binding (GO:0031625), E-box binding (GO:0070888), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Circadian clock	5

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of gene expression	2
circadian rhythm	2
negative regulation of DNA-templated transcription	1
sodium ion transport	1
regulation of metal ion transport	1
chromatin organization	1
rhythmic process	1
response to external stimulus	1
regulation of circadian rhythm	1
hair cycle	1
regulation of multicellular organismal process	1
regulation of biological process	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
photoperiodism	1
entrainment of circadian clock	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
JNK cascade	1
negative regulation of MAPK cascade	1
regulation of JNK cascade	1
response to purine-containing compound	1
response to organophosphorus	1
response to oxygen-containing compound	1
regulation of cytokine production	1
cytokine production involved in inflammatory response	1
p38MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular steroid hormone receptor signaling pathway	1
nuclear receptor-mediated glucocorticoid signaling pathway	1
regulation of nuclear receptor-mediated glucocorticoid signaling pathway	1
biological_process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1

Protein interactions and networks

STRING

713 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PER1	CRY2	Q49AN0	841
PER1	CRY1	Q16526	822
PER1	TIMELESS	Q9UNS1	718
PER1	NR1D1	P20393	710
PER1	CSNK1E	P49674	672
PER1	CHEK2	O96017	648
PER1	NR1D2	Q14995	643
PER1	NPAS1	Q99742	631
PER1	RORA	P35397	557
PER1	RORB	Q92753	552
PER1	NFIL3	Q16649	511
PER1	BHLHE41	Q9C0J9	505
PER1	ADORA2B	P29275	505
PER1	SIM1	P81133	493
PER1	BHLHE40	O14503	484

IntAct

186 interactions, top by confidence:

A	B	Type	Score
CSNK1E	PER2	psi-mi:“MI:0914”(association)	0.850
CSNK1E	PER1	psi-mi:“MI:0914”(association)	0.840
CSNK1D	PER2	psi-mi:“MI:0914”(association)	0.810
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
KBTBD7	METTL15	psi-mi:“MI:0914”(association)	0.730
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.670
FOXK2	DVL2	psi-mi:“MI:0914”(association)	0.640
QPRT	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
PER1	CRY1	psi-mi:“MI:0915”(physical association)	0.560
Cry1	PER1	psi-mi:“MI:0915”(physical association)	0.560
PER1	APBB2	psi-mi:“MI:0915”(physical association)	0.560
PER1	CASP6	psi-mi:“MI:0915”(physical association)	0.560
PER1	EEF1D	psi-mi:“MI:0915”(physical association)	0.560
PER1		psi-mi:“MI:0915”(physical association)	0.560
PER1	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
PER1	ERN1	psi-mi:“MI:0915”(physical association)	0.560
PER1	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
PER1	FKBP1A	psi-mi:“MI:0915”(physical association)	0.560
PER1	GFAP	psi-mi:“MI:0915”(physical association)	0.560
PER1	GRN	psi-mi:“MI:0915”(physical association)	0.560
GRIN2C	PER1	psi-mi:“MI:0915”(physical association)	0.560
PER1	GSN	psi-mi:“MI:0915”(physical association)	0.560
PER1	HRAS	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (132): RBPMS (Two-hybrid), PER1 (Two-hybrid), PER1 (Two-hybrid), PER1 (Two-hybrid), PER1 (Two-hybrid), PER1 (Two-hybrid), PER1 (Affinity Capture-MS), PER1 (Affinity Capture-MS), PER1 (Affinity Capture-MS), PER1 (Affinity Capture-MS), PRKACB (Affinity Capture-MS), CRY1 (Affinity Capture-MS), PER1 (Affinity Capture-MS), PER1 (Affinity Capture-MS), PER1 (Affinity Capture-MS)

ESM2 similar proteins: A1YF56, A2AEV7, A6NCS4, A7Y7W2, D3ZJK7, E1BEA8, F1MUS9, O15534, O35973, O43435, O43638, O60248, O75333, O77728, O94983, O95935, O95947, P22736, P46099, P51666, P56261, P57082, P70325, P70327, Q03484, Q0V8F0, Q15744, Q497V6, Q5DTT2, Q61660, Q61663, Q63HR2, Q64731, Q66JL1, Q6PZD9, Q6ZQN5, Q80Y50, Q810F8, Q861Q9, Q8AV66

Diamond homologs: O15055, O15534, O35973, O54943, O70361, P56645, Q8CHI5, Q8CJE2, Q8K3T2, Q8K3T3, Q8QGQ8, Q9Z301, P07663, Q03297, Q03353, Q03354, Q03355, Q24767, Q2VPD4, P12348, P97460, O02748, O61735, P12349, P27540, P41739, Q25478, Q25637, Q5ZQU2, Q61324, Q65ZG8, Q78E60, Q99743, Q9BE97, Q9DG12, Q9HBZ2, P91607, P91613, P91686, P91697

SIGNOR signaling

18 interactions.

A	Effect	B	Mechanism
CSNK1E	down-regulates	PER1	phosphorylation
CSNK1G2	down-regulates	PER1	phosphorylation
BTRC	down-regulates	PER1	ubiquitination
FBXW11	down-regulates	PER1	ubiquitination
PER1	“down-regulates quantity by repression”	SLC5A1	“transcriptional regulation”
TNPO1	“up-regulates activity”	PER1	relocalization
BMAL1/NPAS2	“up-regulates quantity by expression”	PER1	“transcriptional regulation”
PER1	“down-regulates activity”	BMAL1/NPAS2	binding
PER1	“down-regulates activity”	CLOCK/BMAL1	binding
CSNK1D	“down-regulates quantity by destabilization”	PER1	phosphorylation
NR3C1	“up-regulates quantity by expression”	PER1	“transcriptional regulation”
NFIL3	“down-regulates quantity by repression”	PER1	“transcriptional regulation”
CSNK1A1	“down-regulates quantity by destabilization”	PER1	phosphorylation
CSNK1E	“down-regulates quantity by destabilization”	PER1	phosphorylation
ARNTL	“up-regulates quantity by expression”	PER1	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	PER1	“transcriptional regulation”
CLOCK/BMAL1	“up-regulates quantity by expression”	PER1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 116 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	7	70.4×	1e-09
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	5	33.5×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
circadian regulation of gene expression	8	18.7×	8e-06
regulation of circadian rhythm	5	13.0×	8e-03
circadian rhythm	5	12.2×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	182
Likely benign	24
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

8274 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:8147741:A:G	W441R	1.000
17:8147741:A:T	W441R	1.000
17:8148199:A:G	F370S	1.000
17:8148229:A:G	F360S	1.000
17:8141887:A:G	F1173S	0.999
17:8147687:G:C	H459D	0.999
17:8147692:C:T	G457D	0.999
17:8147693:C:G	G457R	0.999
17:8147739:C:A	W441C	0.999
17:8147739:C:G	W441C	0.999
17:8147740:C:G	W441S	0.999
17:8147758:A:T	V435D	0.999
17:8148029:T:A	D401V	0.999
17:8148029:T:G	D401A	0.999
17:8148030:C:G	D401H	0.999
17:8148068:A:G	L388P	0.999
17:8148086:C:A	G382V	0.999
17:8148086:C:T	G382D	0.999
17:8148087:C:G	G382R	0.999
17:8148206:A:G	C368R	0.999
17:8148223:G:T	T362K	0.999
17:8148228:G:C	F360L	0.999
17:8148228:G:T	F360L	0.999
17:8148230:A:G	F360L	0.999
17:8148739:A:G	L318P	0.999
17:8150006:A:G	L165P	0.999
17:8141846:A:G	W1187R	0.998
17:8141846:A:T	W1187R	0.998
17:8147477:A:G	L497P	0.998
17:8147555:A:G	F471S	0.998

dbSNP variants (sampled 300 via entrez): RS1000050064 (17:8152390 C>G), RS1000522008 (17:8153623 A>G), RS1000580530 (17:8144174 T>G), RS1000956222 (17:8153356 C>A,T), RS1001072272 (17:8140714 C>T), RS1001078744 (17:8142997 A>G), RS1001186877 (17:8145219 T>A,C), RS1001386956 (17:8149618 A>C,G), RS1001683786 (17:8140580 G>A), RS1001722712 (17:8145457 G>C,T), RS1002061299 (17:8144325 C>A), RS1002074541 (17:8142082 G>A), RS1002113669 (17:8144108 C>T), RS1002343693 (17:8150836 C>T), RS1002364811 (17:8153936 T>C,G)

Disease associations

OMIM: gene MIM:602260 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010242_175	HDL cholesterol levels	2.000000e-11
GCST90002386_177	High light scatter reticulocyte percentage of red cells	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Dexamethasone	increases expression, affects cotreatment	4
Progesterone	decreases reaction, increases expression	3
entinostat	increases expression, affects cotreatment	2
KL001	decreases reaction, increases expression, decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Benzo(a)pyrene	affects cotreatment, increases expression, increases methylation, decreases reaction	2
Hydrogen Peroxide	affects cotreatment, affects expression, affects reaction	2
Valproic Acid	affects expression, increases methylation	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
PF-06840003	decreases expression, decreases reaction	1
sotorasib	decreases expression, affects cotreatment	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
tulobuterol	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
mangiferin	affects expression, affects reaction	1
sodium bichromate	increases expression	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	affects cotreatment, increases expression, decreases reaction	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
didecyldimethylammonium	increases expression	1
perfluorodecanoic acid	decreases expression	1
epigallocatechin gallate	affects cotreatment, affects expression, affects reaction	1
15-acetyldeoxynivalenol	increases expression	1
gallocatechol	affects cotreatment, affects expression, affects reaction	1
epicatechin gallate	affects reaction, affects cotreatment, affects expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8MF	Abcam HCT 116 PER1 KO	Cancer cell line	Male
CVCL_B9A6	Abcam MCF-7 PER1 KO	Cancer cell line	Female
CVCL_B9PL	Abcam A-549 PER1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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