CREM

Summary

CREM (cAMP responsive element modulator, HGNC:2352) is a protein-coding gene on chromosome 10p11.21, encoding cAMP-responsive element modulator (Q03060). Transcriptional regulator that binds the cAMP response element (CRE), a sequence present in many viral and cellular promoters.

This gene encodes a bZIP transcription factor that binds to the cAMP responsive element found in many viral and cellular promoters. It is an important component of cAMP-mediated signal transduction during the spermatogenetic cycle, as well as other complex processes. Alternative promoter and translation initiation site usage allows this gene to exert spatial and temporal specificity to cAMP responsiveness. Multiple alternatively spliced transcript variants encoding several different isoforms have been found for this gene, with some of them functioning as activators and some as repressors of transcription.

Source: NCBI Gene 1390 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 50 total
• Transcription factor: yes — 96 downstream targets (CollecTRI)
• MANE Select transcript: NM_183011

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2352
Approved symbol	CREM
Name	cAMP responsive element modulator
Location	10p11.21
Locus type	gene with protein product
Status	Approved
Aliases	hCREM-2
Ensembl gene	ENSG00000095794
Ensembl biotype	protein_coding
OMIM	123812
Entrez	1390

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 34 protein_coding, 10 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000337656, ENST00000342105, ENST00000344351, ENST00000345491, ENST00000348787, ENST00000354759, ENST00000356917, ENST00000361599, ENST00000374711, ENST00000374721, ENST00000374726, ENST00000374734, ENST00000395887, ENST00000427847, ENST00000429130, ENST00000460270, ENST00000461968, ENST00000463314, ENST00000463960, ENST00000464475, ENST00000466251, ENST00000468236, ENST00000469517, ENST00000469949, ENST00000472813, ENST00000473940, ENST00000474362, ENST00000474931, ENST00000479070, ENST00000482633, ENST00000482646, ENST00000484283, ENST00000487132, ENST00000487763, ENST00000488328, ENST00000488741, ENST00000489321, ENST00000489388, ENST00000490460, ENST00000490511, ENST00000494479, ENST00000495301, ENST00000495960, ENST00000496019, ENST00000496626, ENST00000497686, ENST00000685392, ENST00000686585

RefSeq mRNA: 53 — MANE Select: NM_183011 NM_001267562, NM_001267563, NM_001267564, NM_001267565, NM_001267567, NM_001267570, NM_001352445, NM_001352446, NM_001352465, NM_001352466, NM_001352467, NM_001394595, NM_001394598, NM_001394600, NM_001394602, NM_001394603, NM_001394605, NM_001394608, NM_001394610, NM_001394613, NM_001394614, NM_001394615, NM_001394616, NM_001394617, NM_001394618, NM_001394619, NM_001394620, NM_001394622, NM_001394623, NM_001394625, NM_001394626, NM_001394627, NM_001394628, NM_001394629, NM_001394630, NM_001394631, NM_001881, NM_181571, NM_182717, NM_182718, NM_182719, NM_182720, NM_182721, NM_182723, NM_182724, NM_182769, NM_182770, NM_182771, NM_182772, NM_183011, NM_183012, NM_183013, NM_183060

CCDS: CCDS31181, CCDS53517, CCDS53518, CCDS53519, CCDS53520, CCDS53521, CCDS53522, CCDS53523, CCDS58074, CCDS58075, CCDS58076, CCDS7180, CCDS7181, CCDS7182, CCDS7183, CCDS7184, CCDS7185, CCDS7186, CCDS7187, CCDS7188

Canonical transcript exons

ENST00000685392 — 8 exons

Exon	Start	End
ENSE00003469149	35137782	35137879
ENSE00003481920	35179134	35179276
ENSE00003491273	35206895	35207051
ENSE00003652308	35148368	35148491
ENSE00003692802	35178889	35178986
ENSE00003786589	35188200	35188388
ENSE00003932688	35211254	35212953
ENSE00003933510	35126846	35127193

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 99.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.6155 / max 1612.3070, expressed in 1812 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104676	14.5819	1018
104679	5.6946	1220
104667	4.8999	1153
104663	3.8844	1614
104665	3.5350	1567
104677	1.6931	297
104662	1.6848	1109
104664	0.7725	415
104661	0.6631	389
104666	0.6145	222

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	99.22	gold quality
right testis	UBERON:0004534	99.07	gold quality
adrenal tissue	UBERON:0018303	98.01	gold quality
testis	UBERON:0000473	97.61	gold quality
right adrenal gland cortex	UBERON:0035827	97.12	gold quality
left adrenal gland cortex	UBERON:0035825	97.02	gold quality
left adrenal gland	UBERON:0001234	96.99	gold quality
right adrenal gland	UBERON:0001233	96.98	gold quality
adrenal cortex	UBERON:0001235	96.75	gold quality
adrenal gland	UBERON:0002369	96.71	gold quality
sperm	CL:0000019	96.61	gold quality
gall bladder	UBERON:0002110	95.79	gold quality
adenohypophysis	UBERON:0002196	95.70	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.31	gold quality
male germ cell	CL:0000015	95.16	gold quality
omental fat pad	UBERON:0010414	94.78	gold quality
peritoneum	UBERON:0002358	94.73	gold quality
pituitary gland	UBERON:0000007	94.62	gold quality
left uterine tube	UBERON:0001303	94.43	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.78	gold quality
islet of Langerhans	UBERON:0000006	93.75	gold quality
left ovary	UBERON:0002119	93.75	gold quality
cauda epididymis	UBERON:0004360	93.49	gold quality
heart left ventricle	UBERON:0002084	93.35	gold quality
right lung	UBERON:0002167	93.35	gold quality
cardiac ventricle	UBERON:0002082	93.21	gold quality
stromal cell of endometrium	CL:0002255	93.18	gold quality
caudate nucleus	UBERON:0001873	93.14	gold quality
right atrium auricular region	UBERON:0006631	92.88	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-CURD-95	yes	4443.03
E-HCAD-29	yes	4068.81
E-GEOD-135922	yes	2538.14
E-HCAD-8	yes	2453.26
E-MTAB-7407	yes	2086.63
E-CURD-120	yes	1513.63
E-MTAB-10596	yes	1448.40
E-MTAB-8142	yes	80.98
E-HCAD-1	yes	48.07
E-CURD-88	yes	45.69
E-HCAD-10	yes	42.45
E-CURD-46	yes	38.52
E-GEOD-134144	yes	32.22
E-CURD-122	yes	24.75
E-CURD-112	yes	18.31

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

96 targets.

Target	Regulation
AANAT	Unknown
ABCC8
ACE	Activation
ACOT7	Unknown
ACR	Unknown
ADAM2
ADRA1D
ADRB1	Unknown
AGTR1
AGTRAP
AP1	Repression
APRT
BCL2	Repression
BGLAP
BRAF
CALM1
CAMK4
CCK
CCL4	Repression
CCNA1	Unknown
CCNA2	Repression
CCND1	Unknown
CD247	Repression
CD86
CD8A
CD8B
CELA2A
CHGA
CISH
CNTN2

JASPAR motifs

Motif	Name	Family
MA0609.2	CREM	CREB-related factors
MA0609.3	CREM	CREB-related factors

JASPAR matrix evidence (PMIDs): PMID:20920259

Upstream regulators (CollecTRI, top): AP1, CREB1, CREM, FOS, FOXP3, JUN, SP1, STAT1

miRNA regulators (miRDB)

43 targeting CREM, 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-4282	99.99	75.36	6408
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-513A-3P	99.39	70.63	3620

Literature-anchored findings (GeneRIF, showing 40)

• review of CREM transcription factor involvement with spermatogenesis (PMID:11988318)
• Increased expression of CREM in T cells from systemic lupus erythmatosus (SLE) patients results from increased transcriptional activity of the CREM gene, and its binding to IL-2 promoter is responsible for decreased production of IL-2 by SLE T cells. (PMID:12370343)
• 5’-RACE on human testis cDNA indicated that exon theta2 is > or = 113 bp in size. In-vitro translation of CREM-theta1 and CREM-theta2 splice variants cloned from human testis yielded full length proteins and also shorter repressor products (PMID:12397208)
• Direct binding of CREM to the CRE site of the IL-2 promoter endows CREM with a central role in repression of IL-2 gene expression: CREM binding promotes chromatin deacetylation, limits promoter accessibility and decreases its transcriptional activity. (PMID:12626549)
• expression of cAMP-responsive element modulator(CREM) activators is a prerequisite for normal spermatogenesis, and the lack of CREM activator expression results in male infertility (PMID:14511788)
• CREB-1/CREM-1 have roles as regulators of macrophage differentiation (PMID:14754893)
• These findings provide little additional evidence for a susceptibility locus for panic disorder either within the CREM gene or in a nearby region of chromosome 10p11 in our sample (PMID:15048659)
• Sperm nucleus PHGPx expression is mediated by the transcription factor CREM-tau, which acts as a cis-acting element localized in the first intron of the PHGPx gene. [CREM-tau] (PMID:15225122)
• down-regulation of CREMtau-mediated gene expression by GCNF (PMID:15456763)
• Lack of spermatid elongation was not due to defective CREM expression. Therefore, CREM did not play a pathogenetic role in the onset of SMA in humans. (PMID:15474076)
• that heart-directed expression of CREM-IbDeltaC-X leads to complex cardiac alterations, suggesting CREM as a central regulator of cardiac morphology, function, and gene expression (PMID:15569686)
• isoforms regulate discrete groups of genes in myometrium (PMID:15691874)
• Results identify calcium/calmodulin-dependent kinase IV as being responsible for the increased expression of CREM and the decreased production of interleukin-2 in systemic lupus erythematosus T cells. (PMID:15841182)
• CREM activator and repressor isoforms were found in all germ cell types, but not in Sertoli cells; data suggest a fine-tuning between CREM activator and repressor isoforms in normal germ cells that might be disturbed during impaired spermatogenesis (PMID:16048633)
• SRp40 regulates the switch in splicing from production of CREMtau(2)alpha to CREMalpha (PMID:16103121)
• Screening of a substantial number of patients would be required to clarify whether observed combinations of genetic changes in the CREM gene might explain some forms of male infertility. (PMID:16143638)
• The interaction between CREM and one haplotype of ACT (activator of CREM in the testis) was reduced by 45% in a yeast two-hybrid assay. (PMID:16687568)
• HNF4alpha, CREM, HNF1alpha, and C/EBPalpha have roles in transcriptional regulation of the glucose-6-phosphatase gene by cAMP/vasoactive intestinal peptide in the intestine (PMID:16893891)
• These results constitute the first demonstration of the transcriptional control of ATP1A4 gene expression by cAMP and by CREMtau, a transcription factor essential for male germ cell gene expression. (PMID:16894555)
• functional analysis of isoforms from the testes (PMID:16899810)
• CREMalpha exerts its repressor activity by a mechanism that involves recruitment of HDAC1, increased deacetylation of histones, and repression of promoter activity. (PMID:17056544)
• CREM-alpha mRNA levels were higher in T cells from patients with systemic lupus erythematosus than controls while CREB mRNA levels did not differ between the two groups (PMID:17211988)
• The positive-feedback loop described in this review is regulated by phosphodiesterase 3A and ICER and is pathologically important in adult hearts. (PMID:17332439)
• Data show that inducible cAMP early repressor splice variants ICER I and IIgamma both repress transcription of c-fos and chromogranin A. (PMID:17340624)
• Transcription factors of the CREB/CREM/ATF family have a moderate effect on human MC2-R promoter activity, but seem to play a minor role in transmitting stimulation of the cAMP pathway to increased MC2-R expression. (PMID:17712720)
• CREM is an essential regulator of NIS gene expression. (PMID:18202121)
• CREM has a role in CYP1A1 induction through ligand-independent activation pathway of aryl hydrocarbon receptor in HepG2 cells (PMID:18700132)
• CREB/ICER expression needs to be considered a pathogenetic feature in leukemogenesis (PMID:18784739)
• BDNF- and seizure-dependent phosphorylation of STAT3 cause the adenosine 3’,5’-monophosphate (cAMP) response element-binding protein (CREB) family member ICER (inducible cAMP early repressor) to bind with phosphorylated CREB at the Gabra1:CRE site. (PMID:18922788)
• CREMalpha is an important negative regulator of costimulation and APC-dependent T cell function (PMID:19299714)
• This review will bring together data on ICER and its functions in the brain, with a special emphasis on recent findings highlighting the involvement of ICER in the regulation of long-term plasticity underlying learning and memory. [REVIEW] (PMID:19434522)
• cAMP stringently regulates human cathelicidin antimicrobial peptide expression in the mucosal epithelial cells by activating cAMP-response element-binding protein, AP-1, and inducible cAMP early repressor (PMID:19531482)
• DNA cytosine methylation in the bovine leukemia virus promoter has a role in direct inhibition of cAMP-responsive element (CRE)-binding protein/CRE modulator/activation transcription factor binding (PMID:20413592)
• Results indicate that SPAG8 acts as a regulator of ACT and plays an important role in CREM-ACT-mediated gene transcription during spermatogenesis. (PMID:20488182)
• anscriptional activation of the cAMP-responsive modulator promoter in human T cells is regulated by protein phosphatase 2A-mediated dephosphorylation of SP-1 and reflects disease activity in patients with systemic lupus erythematosus. (PMID:21097497)
• ICER mediates chemotherapy anticancer activity through DUSP1-p38 pathway activation and drives the cell program from survival to apoptosis (PMID:21325296)
• Patients with two types of male factor infertility display an increased abnormal methylation of CREM compared with control subjects. (PMID:21507395)
• Induction of ICER links oxidative stress to beta cell failure caused by oxidised LDL, and it can be effectively abrogated by antioxidant treatment. (PMID:21547497)
• AP-1-dependent up-regulation of the P2 promoter, SLE T cells fail to further increase their basal CREM levels upon T cell activation due to a decreased content of the AP-1 family member c-Fos (PMID:21757709)
• Phosphorylation of ICER on a discrete residue targeted ICER to be monoubiquitinated. (PMID:21767532)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	crema	ENSDARG00000023217
mus_musculus	Crem	ENSMUSG00000063889
rattus_norvegicus	Crem	ENSRNOG00000014900
drosophila_melanogaster	CrebA	FBGN0004396
drosophila_melanogaster	Atf6	FBGN0033010
drosophila_melanogaster	CrebB	FBGN0265784
caenorhabditis_elegans		WBGENE00000222
caenorhabditis_elegans		WBGENE00000793
caenorhabditis_elegans		WBGENE00016162

Paralogs (9): CREB3L3 (ENSG00000060566), CREB3 (ENSG00000107175), ATF6 (ENSG00000118217), CREB1 (ENSG00000118260), ATF1 (ENSG00000123268), CREB3L4 (ENSG00000143578), CREB3L1 (ENSG00000157613), CREB3L2 (ENSG00000182158), ATF6B (ENSG00000213676)

Protein

Protein identifiers

cAMP-responsive element modulator — Q03060 (reviewed: Q03060)

Alternative names: Inducible cAMP early repressor

All UniProt accessions (14): Q03060, A0A0A0MSU8, C9IYM9, C9J2J0, C9J5A7, C9K092, E9PAR2, E9PB41, F8WB03, F8WDF2, G5E998, H7C4X0, J3KR46, R4GN75

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator that binds the cAMP response element (CRE), a sequence present in many viral and cellular promoters. Isoforms are either transcriptional activators or repressors. Plays a role in spermatogenesis and is involved in spermatid maturation. May play a role in the regulation of the circadian clock: acts as a transcriptional repressor of the core circadian component PER1 by directly binding to cAMP response elements in its promoter.

Subunit / interactions. Binds DNA as a dimer. Interacts with FHL5. Interacts with CDC34. May interact with TSSK4.

Subcellular location. Nucleus Cytoplasm. Nucleus.

Tissue specificity. Expressed in testes (round spermatids) (at protein level). Isoform 14 is the major activator form in testes.

Post-translational modifications. Isoform 9 is ubiquitinated by CDC34 and RAD6B in order to be degraded by the proteasome. Stimulated by phosphorylation. Phosphorylated on Ser-116 by TSSK4 in vitro.

Miscellaneous. Produced by alternative promoter usage. Produced by alternative splicing of isoform 1. Activator. Produced by alternative splicing of isoform 1. Activator. Produced by alternative splicing of isoform 1. Produced by alternative promoter usage. Activator. Produced by alternative promoter usage. Repressor. Produced by alternative splicing of isoform 6. Repressor. Produced by alternative splicing of isoform 6. Repressor. Produced by alternative splicing of isoform 6. Repressor. Produced by alternative promoter usage. Activator. Produced by alternative splicing of isoform 10. Repressor. Produced by alternative splicing of isoform 5. Repressor. Produced by alternative splicing of isoform 1. Activator. Produced by alternative splicing of isoform 1. Activator. Produced by alternative splicing of isoform 1. Repressor. Produced by alternative splicing of isoform 1. Repressor. Produced by alternative splicing of isoform 1. Repressor. Produced by alternative splicing of isoform 1. Repressor. Produced by alternative splicing of isoform 10. Activator. Produced by alternative splicing. Produced by alternative splicing. Produced by alternative splicing. Produced by alternative splicing. Produced by alternative splicing. Produced by alternative splicing.

Similarity. Belongs to the bZIP family.

Isoforms (29)

UniProt ID	Names	Canonical?
Q03060-5	1, CREM-BCEFGgammaHIbeta	yes
Q03060-1	2, Beta, CREM-BCEFGHIbeta
Q03060-6	3, CREM-BCEFGIalpha, Tau
Q03060-2	4, Alpha, CREM-BEFHIb, CREM-gamma
Q03060-7	5, CREM-theta2tau-gamma, CREM-theta2EFGHIb
Q03060-8	6, CREM2alpha-a, IcergammaHIalpha, ICER1, ICERI
Q03060-9	7, CREM2alpha-b, IcerHIalpha, ICERIgamma
Q03060-10	8, CREM 2beta-a, IcergammaHIbeta, ICERII
Q03060-11	9, CREM 2beta-b, IcerHIbeta, ICERIIgamma
Q03060-12	10, CREMtheta1tau2beta, CREM-theta1EFGHIbeta
Q03060-13	11, CREM-theta1beta, CREM-theta1EFHIbeta
Q03060-14	12, CREM-theta2beta, CREM-theta2EFHIb, CREM-theta2-gamma
Q03060-15	13, CREM-BEFGgammaHIbeta
Q03060-16	14, CREM-tau2-gamma, CREM-BEFGHIbeta
Q03060-17	15, CREM-BGHIbeta
Q03060-19	16, CREM-deltaC-G, CREM-BgammaHIbeta
Q03060-20	17, CREM-BHIbeta
Q03060-21	18, CREM-BHIalpha
Q03060-22	19, CREM-theta1tau2gamma, CREM-theta1EFGgammaHIbeta
Q03060-23	20
Q03060-24	21
Q03060-25	22
Q03060-26	23
Q03060-27	24
Q03060-28	25
Q03060-29	26
Q03060-30	27
Q03060-31	28
Q03060-32	29

RefSeq proteins (51): NP_001254491, NP_001254492, NP_001254493, NP_001254496, NP_001254499, NP_001339374, NP_001339375, NP_001339394, NP_001339395, NP_001339396, NP_001381524, NP_001381527, NP_001381529, NP_001381531, NP_001381532, NP_001381534, NP_001381537, NP_001381539, NP_001381542, NP_001381543, NP_001381544, NP_001381545, NP_001381546, NP_001381547, NP_001381548, NP_001381549, NP_001381551, NP_001381552, NP_001381554, NP_001381555, NP_001381556, NP_001381557, NP_001381558, NP_001381560, NP_001872, NP_853549, NP_874386, NP_874387, NP_874388, NP_874389, NP_874390, NP_874392, NP_874393, NP_877570, NP_877571, NP_877572, NP_877573, NP_898829, NP_898830, NP_898831, NP_898883 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001630	Leuzip_CREB	Family
IPR003102	CREB1-like_pKID	Domain
IPR004827	bZIP	Domain
IPR046347	bZIP_sf	Homologous_superfamily

Pfam: PF00170, PF02173

UniProt features (39 total): splice variant 21, sequence conflict 7, modified residue 5, domain 2, region of interest 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q03060-F1	61.54	0.24

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 (5): 102, 129, 271, 274, 277

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes

MSigDB gene sets: 402 (showing top): ATF_B, YAATNRNNNYNATT_UNKNOWN, WALLACE_PROSTATE_CANCER_RACE_UP, AMIT_DELAYED_EARLY_GENES, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, ATACCTC_MIR202, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, MAZ_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, CREBP1_Q2, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_MALE_GAMETE_GENERATION, FOXO1_01, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), glycosphingolipid metabolic process (GO:0006687), signal transduction (GO:0007165), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944), rhythmic process (GO:0048511), cAMP/PKA signal transduction (GO:0141156)

GO Molecular Function (9): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), 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 repressor activity, RNA polymerase II-specific (GO:0001227), DNA binding (GO:0003677), cAMP response element binding protein binding (GO:0008140), sequence-specific double-stranded DNA binding (GO:1990837), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737), membrane (GO:0016020), ATF4-CREB1 transcription factor complex (GO:1990589), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Circadian clock	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
negative regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
glycolipid metabolic process	1
sphingolipid metabolic process	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
cellular developmental process	1
positive regulation of DNA-templated transcription	1
biological_process	1
intracellular signaling cassette	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
nucleic acid binding	1
DNA-binding transcription factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
transcription regulator activity	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
RNA polymerase II transcription regulator complex	1
protein-containing complex	1

Protein interactions and networks

STRING

2040 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CREM	FHL5	Q5TD97	901
CREM	CREB1	P16220	859
CREM	KIF17	Q9P2E2	791
CREM	CREBBP	Q92793	787
CREM	HBZ	P02008	758
CREM	TBPL1	P62380	703
CREM	A0A0B4J2F2	A0A0B4J2F2	644
CREM	GDNF	P39905	629
CREM	SIK1	P57059	600
CREM	IL2	P01585	594
CREM	ACR	P10323	590
CREM	FOS	P01100	570
CREM	EP300	Q09472	558
CREM	ATF3	P18847	557
CREM	PIWIL1	Q96J94	546

IntAct

33 interactions, top by confidence:

A	B	Type	Score
CREM		psi-mi:“MI:0914”(association)	0.530
IL2	CREM	psi-mi:“MI:0914”(association)	0.530
CREM	IL2	psi-mi:“MI:0914”(association)	0.530
	CREM	psi-mi:“MI:0914”(association)	0.530
MIA2	RGPD3	psi-mi:“MI:0914”(association)	0.530
CREM		psi-mi:“MI:0915”(physical association)	0.500
	CREM	psi-mi:“MI:0915”(physical association)	0.500
	CREM	psi-mi:“MI:0914”(association)	0.500
SP100	CREM	psi-mi:“MI:0915”(physical association)	0.490
HDAC1	CREM	psi-mi:“MI:0915”(physical association)	0.400
CREM	Hdac1	psi-mi:“MI:0915”(physical association)	0.400
CREM	DNMT3A	psi-mi:“MI:0915”(physical association)	0.400
DNMT3A	CREM	psi-mi:“MI:0915”(physical association)	0.400
CREM		psi-mi:“MI:0915”(physical association)	0.400
	CREM	psi-mi:“MI:0915”(physical association)	0.400
EMP3	CREM	psi-mi:“MI:0915”(physical association)	0.370
CREM	UBE2I	psi-mi:“MI:0915”(physical association)	0.370
CREM	CASP8AP2	psi-mi:“MI:0915”(physical association)	0.370
PIAS3	CREM	psi-mi:“MI:0915”(physical association)	0.370
CREM	ATXN1	psi-mi:“MI:0915”(physical association)	0.370
	CREM	psi-mi:“MI:0914”(association)	0.350
CREM	IL17F	psi-mi:“MI:0914”(association)	0.350
CREM	IL17A	psi-mi:“MI:0914”(association)	0.350
IL17A	CREM	psi-mi:“MI:0914”(association)	0.350
CREM		psi-mi:“MI:0914”(association)	0.350

BioGRID (86): CREM (Reconstituted Complex), CREM (Two-hybrid), CREM (Affinity Capture-MS), CREM (Affinity Capture-MS), CREM (Affinity Capture-MS), CREM (Affinity Capture-MS), CREM (Reconstituted Complex), CREM (Affinity Capture-Western), SP1 (Reconstituted Complex), CREM (Affinity Capture-MS), CREM (Affinity Capture-MS), CREM (Affinity Capture-MS), CREM (Two-hybrid), NCALD (Two-hybrid), NCS1 (Two-hybrid)

ESM2 similar proteins: A6QQW0, B4F7E9, O15391, O43167, O62836, O70230, O70494, P08048, P15337, P17010, P17012, P18846, P20385, P25490, P27699, P36508, P52747, P79145, P81069, P81269, Q00420, Q00899, Q01147, Q01611, Q02447, Q03060, Q03061, Q06547, Q08DA8, Q0V8G2, Q1LYE3, Q1LZH5, Q1RMI3, Q4V8R6, Q52KB5, Q52V16, Q58DZ6, Q5XIU2, Q66K89, Q6B4Z5

Diamond homologs: P15337, P16220, P18846, P27699, P27925, P51984, P51985, P79145, P81269, Q01147, Q03060, Q03061, Q08DA8, Q1LZH5, Q66HA2, Q96BA8, Q9U2I0, Q9VWW0, Q9Z125, A1L224, A2VD01, O43889, O44743, P29747, Q08CW8, Q1LYG4, Q3SYZ3, Q4JFH9, Q502F0, Q5FVM5, Q5RCM9, Q5UEM7, Q5UEM8, Q61817, Q68CJ9, Q6QDP7, Q70SY1, Q8BH52, Q8SQ19, Q8TEY5

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
FHL5	“up-regulates activity”	CREM	binding
CREM	“down-regulates quantity by repression”	IL2	“transcriptional regulation”
CDK1	“down-regulates quantity”	CREM	phosphorylation
MAPK3	“down-regulates quantity by destabilization”	CREM	phosphorylation
CDK1	“down-regulates quantity by destabilization”	CREM	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

2157 predictions. Top by Δscore:

Variant	Effect	Δscore
10:35127565:GAA:G	donor_gain	1.0000
10:35127568:G:GG	donor_gain	1.0000
10:35127580:GATT:G	donor_gain	1.0000
10:35148362:TTTCA:T	acceptor_loss	1.0000
10:35148363:TTCAG:T	acceptor_loss	1.0000
10:35148364:TCAG:T	acceptor_loss	1.0000
10:35148365:CAGAC:C	acceptor_loss	1.0000
10:35148366:A:AG	acceptor_gain	1.0000
10:35148366:A:T	acceptor_loss	1.0000
10:35148367:G:GC	acceptor_loss	1.0000
10:35148367:G:GG	acceptor_gain	1.0000
10:35148367:GA:G	acceptor_gain	1.0000
10:35148367:GAC:G	acceptor_gain	1.0000
10:35148367:GACA:G	acceptor_gain	1.0000
10:35148367:GACAA:G	acceptor_gain	1.0000
10:35148406:G:GT	donor_gain	1.0000
10:35179132:A:AG	acceptor_gain	1.0000
10:35179133:G:GG	acceptor_gain	1.0000
10:35179133:GGAAA:G	acceptor_gain	1.0000
10:35179277:GTAT:G	donor_gain	1.0000
10:35206890:T:A	acceptor_gain	1.0000
10:35206891:GCA:G	acceptor_loss	1.0000
10:35206892:CAG:C	acceptor_loss	1.0000
10:35206893:A:AG	acceptor_gain	1.0000
10:35206894:G:GT	acceptor_gain	1.0000
10:35206894:GC:G	acceptor_gain	1.0000
10:35206894:GCT:G	acceptor_gain	1.0000
10:35206894:GCTGC:G	acceptor_gain	1.0000
10:35207032:C:G	donor_gain	1.0000
10:35207049:CAG:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000022950 (10:35132082 T>C), RS1000069706 (10:35126713 C>T), RS1000074583 (10:35181201 C>A), RS1000092954 (10:35201862 T>C), RS1000121464 (10:35134145 C>A), RS1000127975 (10:35174393 G>A,T), RS1000163828 (10:35193104 A>G), RS1000184897 (10:35159116 T>G), RS1000206235 (10:35198327 A>G), RS1000209558 (10:35148807 G>A,C), RS1000261448 (10:35167884 A>G), RS1000275687 (10:35155617 T>C), RS1000322880 (10:35158823 T>G), RS1000347041 (10:35147046 T>TG,TGTG), RS1000417998 (10:35153108 A>T)

Disease associations

OMIM: gene MIM:123812 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000879_19	Crohn’s disease	1.000000e-09
GCST001725_105	Inflammatory bowel disease	2.000000e-25
GCST004131_87	Inflammatory bowel disease	6.000000e-12
GCST004132_106	Crohn’s disease	4.000000e-14
GCST005537_186	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	5.000000e-29
GCST007109_1	Diarrhoea-associated Entamoeba histolytica infection	6.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, affects expression, decreases reaction, increases expression	4
Estradiol	affects cotreatment, decreases expression, increases expression	4
bisphenol A	decreases expression, increases methylation	3
sodium arsenite	increases abundance, increases expression, increases activity, affects methylation, affects cotreatment	3
Valproic Acid	affects expression, decreases methylation, increases expression	3
Cadmium Chloride	decreases expression, increases expression	3
nickel sulfate	increases expression	2
torcetrapib	increases expression	2
Acetaminophen	increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Copper	increases expression, affects binding, decreases expression	2
Dinitrochlorobenzene	increases expression	2
Nickel	increases expression, decreases reaction, affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Thiram	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
cinnamaldehyde	increases expression	1
cobaltous chloride	increases expression	1
ammonium hexachloroplatinate	increases expression	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases reaction, increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
bathocuproine sulfonate	decreases reaction, increases expression, affects cotreatment	1
4-phenylenediamine	increases expression	1
cupric oxide	increases expression	1
15-acetyldeoxynivalenol	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1122	CHL-1	Cancer cell line	Female
CVCL_1992	COLO 699	Cancer cell line	Female
CVCL_1993	COLO 699N	Cancer cell line	Female
CVCL_V643	CHL-2	Cancer cell line	Female

Clinical trials (associated diseases)

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