ZC3H12A

Summary

ZC3H12A (zinc finger CCCH-type containing 12A, HGNC:26259) is a protein-coding gene on chromosome 1p34.3, encoding Endoribonuclease ZC3H12A (Q5D1E8). Endoribonuclease involved in various biological functions such as cellular inflammatory response and immune homeostasis, glial differentiation of neuroprogenitor cells, cell death of cardiomyocytes, adipogenesis and angiogenesis.

ZC3H12A is an MCP1 (CCL2; MIM 158105)-induced protein that acts as a transcriptional activator and causes cell death of cardiomyocytes, possibly via induction of genes associated with apoptosis.

Source: NCBI Gene 80149 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 73 total
• MANE Select transcript: NM_025079

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26259
Approved symbol	ZC3H12A
Name	zinc finger CCCH-type containing 12A
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23231, MCPIP1, Regnase-1
Ensembl gene	ENSG00000163874
Ensembl biotype	protein_coding
OMIM	610562
Entrez	80149

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000373087, ENST00000471012, ENST00000472312, ENST00000640233, ENST00000855881, ENST00000855882, ENST00000855883, ENST00000928884

RefSeq mRNA: 3 — MANE Select: NM_025079 NM_001323550, NM_001323551, NM_025079

CCDS: CCDS417

Canonical transcript exons

ENST00000373087 — 6 exons

Exon	Start	End
ENSE00001079206	37482434	37482540
ENSE00001226762	37480290	37480429
ENSE00001459483	37482737	37484377
ENSE00001459487	37475459	37475939
ENSE00003252104	37481601	37481835
ENSE00003804009	37474580	37474629

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 94.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.8515 / max 1598.8469, expressed in 1800 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2203	36.4100	1750
2202	1.7900	868
2208	0.3333	176
2207	0.3182	152

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	94.94	gold quality
skin of abdomen	UBERON:0001416	94.01	gold quality
mucosa of stomach	UBERON:0001199	92.79	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.47	gold quality
skin of leg	UBERON:0001511	92.00	gold quality
cartilage tissue	UBERON:0002418	91.48	gold quality
granulocyte	CL:0000094	91.47	gold quality
left uterine tube	UBERON:0001303	91.32	gold quality
lower esophagus mucosa	UBERON:0035834	91.01	gold quality
upper lobe of left lung	UBERON:0008952	89.90	gold quality
esophagus mucosa	UBERON:0002469	89.77	gold quality
minor salivary gland	UBERON:0001830	89.45	gold quality
body of stomach	UBERON:0001161	89.27	gold quality
zone of skin	UBERON:0000014	89.15	gold quality
upper lobe of lung	UBERON:0008948	88.46	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.91	gold quality
right adrenal gland cortex	UBERON:0035827	87.53	gold quality
transverse colon	UBERON:0001157	87.41	gold quality
mouth mucosa	UBERON:0003729	87.25	gold quality
mucosa of urinary bladder	UBERON:0001259	87.22	silver quality
right adrenal gland	UBERON:0001233	86.86	gold quality
left adrenal gland cortex	UBERON:0035825	86.83	gold quality
ascending aorta	UBERON:0001496	86.65	gold quality
oocyte	CL:0000023	86.56	gold quality
omental fat pad	UBERON:0010414	86.35	gold quality
peritoneum	UBERON:0002358	86.27	gold quality
left adrenal gland	UBERON:0001234	86.22	gold quality
thoracic aorta	UBERON:0001515	86.17	gold quality
right lung	UBERON:0002167	86.04	gold quality
esophagus	UBERON:0001043	86.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	1210.74
E-MTAB-7052	yes	160.65
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
NOS2	Activation

Upstream regulators (CollecTRI, top): ELK1, SRF

miRNA regulators (miRDB)

62 targeting ZC3H12A, 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-9-5P	100.00	72.28	2361
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-888-3P	99.53	69.77	1057
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013

Literature-anchored findings (GeneRIF, showing 40)

• May cause cell death and plays important role in development of ischemic heart disease. Could be a potential target for therapeutic intervention. (PMID:16574901)
• MCPIP1, 2, 3, and 4, encoded by four genes, Zc3h12a, Zc3h12b, Zc3h12c, and Zc3h12d, respectively, regulates macrophage activation. (PMID:18178554)
• MCP-1-induced angiogenesis is mediated via MCPIP, at least in part through transcriptional activation of cdh12 and cdh19 (PMID:18364357)
• data demonstrate the role amyloid precursor protein (APP) has in glial differentiation of NT2 cells through MCP-1(MCP-1)/MCP-1-induced protein (MCPIP) signaling (PMID:19185603)
• Observations provide evidence for a novel negative feedback loop in the activation of NF-kappaB and point to potential significance of MCPIP in the treatment of pathological states that involve disturbances in the functioning of the NF-kappaB system. (PMID:19747262)
• REVIEW: Understanding ZC3H12A gives a comprehensive panorama that promises to improve our understanding of processes in which this gene is involved including autoimmune, infectious and cardiovascular diseases. (PMID:20807520)
• MCPIP1 coordinates SG formation and apoptosis during cellular stress and may play a critical role in immune homeostasis and resolution of macrophage inflammation. (PMID:21971051)
• MCPIP1 ribonuclease antagonizes dicer and terminates microRNA biogenesis through precursor microRNA degradation. (PMID:22055188)
• Our data suggest that Zc3h12a is a novel IL-6 regulator in fibroblast-like synovial cells, which may be involved in the progression of rheumatoid arthritis. (PMID:22132693)
• Data indicate that absence of MCPIP1 exacerbates ischemic brain damage by upregulation of proinflammatory cytokines and that MCPIP1 participates in LPS-induced ischemic stroke tolerance. (PMID:22196138)
• MCPIP-induces differentiation via induction of oxidative stress that leads to ER stress that causes autophagy involved in tube formation. (PMID:22820500)
• Taken together, these data demonstrate that MCPIP1 down-regulates via an ARE-independent pathway (PMID:23185455)
• MCPIP1 can act as a host innate defense via RNase activity for targeting and degrading viral RNA. (PMID:23355615)
• MCPIP1 is regulated by IL-17 and IL-1 (PMID:23658019)
• These results demonstrate that MCPIP may be an important regulator of inflammatory angiogenesis and provide novel mechanistic insights into the link between MCP-1 and cardiovascular diseases. (PMID:24008336)
• The present results show for the first time that the antidicer RNase activity of MCPIP1 is critical in mediating the angiogenic function of MCPIP. (PMID:24048733)
• MCPIP1 acts as an RNase to limit HIV-1 production in resting CD4+ T cells. (PMID:24191027)
• MCPIP1-associated USP10 is essential for negative regulation of NF-kappaB activation. (PMID:24270572)
• Data show that regulator of G protein signaling 2 (RGS2) was stabilized by deubiquitinase monocyte chemotactic protein-induced protein 1 (MCPIP1). (PMID:25187114)
• MCPIP1 may suppress hepatitis C virus replication and hepatitis C virus-mediated proinflammatory responses with infection, which might contribute to the regulation of host defense against the infection and virus-induced inflammation. (PMID:25225661)
• In this review we summarize current progress regarding the specific characteristics of sequences and structures in the 3’ untranslated regions of mRNAs that are recognized by tristetraproline, Roquins, and Regnase-1. (PMID:25955820)
• MCPIP1 and MCPIP4 form a complex but they act independently in regulation of IL-6 mRNA degradation. (PMID:26134560)
• expression of miR-3613-3p might be regulated by MCPIP1 by cleavage of its precursor form. (PMID:26308737)
• In white blood cells from patients with SLE, MCPIP1 expression was elevated, and its expression correlated positively with the IFN score and negatively with the miR-146a transcript level. (PMID:26315540)
• Findings show increased MCP1P expression in a model of Ischemia/Reperfusion Injury (I/R) and suggest a vital role for MCPIP1 in cell migration and apoptosis, resulting in increased angiogenesis and apoptosis during the late stages of I/R. (PMID:26329288)
• demonstrated induction of MCPIP1 in human fibroblasts embedded in the stress-released 3-D collagen matrix, which occurred through activation of mitogen-activated protein kinases, phosphoinositide 3-kinase, and NF-kappaB (PMID:26399696)
• miR-139-mediated downregulation of MCPIP1 promotes IL-6 expression in osteoarthritis. (PMID:26450708)
• Suggest that MCPIP1 may play an important role in cholesterol induced damage in endothelial cells. (PMID:26617772)
• Regnase-1 can be induced by HMGB1 in microglia and negatively regulates HMGB1-mediated neuroinflammation and neuronal toxicity (PMID:27044405)
• both human and cynomolgus monkey MCPIP1 restrict simian immunodeficiency virus replication. Unlike SAMHD1, MCPIP1-mediated HIV-1 restriction cannot be overcome by SIV Vpx. (PMID:27075251)
• IL-17A-mediated induction of MCPIP1 is involved in the regulation of local altered gene expression in suprabasal epidermal layers in psoriasis (PMID:27180111)
• These data revealed that influenza A virus-induced expression of miR-9 negatively regulated MCPIP1 expression and partially acts as a brake on host MCPIP1-mediated antiviral effect. (PMID:27322373)
• SAHA-mediated suppression of the IL-6 expression is achieved through increased recruitment of CEBPalpha to the MCPIP1 promoter and by relieving the miR-9-mediated inhibition of MCPIP1 expression in OA chondrocytes. (PMID:27404795)
• The human conserved stem-loop structure is not sufficient for ZC3H12A-dependent degradation. (PMID:27494113)
• this study uncovered a novel IL-8-dependent mechanism via which MCPIP-1 maintains epithelial homeostasis (PMID:27513529)
• findings provide novel insight into the potential targeting of MCPIP1 or autophagy in the development of potential therapeutic strategies for silicosis (PMID:27782836)
• These findings reveal a new potential function of MCPIP1, suggesting a possible mechanism of fibrosis in pulmonary silicosis. (PMID:27866190)
• propose that KSHV infection inhibits a negative regulator of miRNA biogenesis (MCPIP1) and up-regulates critical miRNA processing components to evade host mechanisms that inhibit expression of viral miRNAs (PMID:27893764)
• MCPIP1 is a potent negative regulator of psoriatic skin inflammation through IL-17A and IL-17C (PMID:27920272)
• data extend knowledge on roles of MCPIP1 in our model and link the protein to regulation of expression and stability of MYCN through decrease of signaling via Akt/mTOR pathway. (PMID:27935099)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	zc3h12aa	ENSDARG00000005271
mus_musculus	Zc3h12a	ENSMUSG00000042677
rattus_norvegicus	Zc3h12a	ENSRNOG00000009131
drosophila_melanogaster	Regnase-1	FBGN0038769
drosophila_melanogaster	CG42360	FBGN0259742
caenorhabditis_elegans		WBGENE00013107
caenorhabditis_elegans	rege-1	WBGENE00016260
caenorhabditis_elegans		WBGENE00021287
caenorhabditis_elegans		WBGENE00021998
caenorhabditis_elegans		WBGENE00022003

Paralogs (6): KHNYN (ENSG00000100441), ZC3H12B (ENSG00000102053), N4BP1 (ENSG00000102921), ZC3H12C (ENSG00000149289), ZC3H12D (ENSG00000178199), NYNRIN (ENSG00000205978)

Protein

Protein identifiers

Endoribonuclease ZC3H12A — Q5D1E8 (reviewed: Q5D1E8)

Alternative names: Monocyte chemotactic protein-induced protein 1, Regnase-1, Zinc finger CCCH domain-containing protein 12A

All UniProt accessions (3): A0A1W2PQC8, Q5D1E8, R4GN17

UniProt curated annotations — full annotation on UniProt →

Function. Endoribonuclease involved in various biological functions such as cellular inflammatory response and immune homeostasis, glial differentiation of neuroprogenitor cells, cell death of cardiomyocytes, adipogenesis and angiogenesis. Functions as an endoribonuclease involved in mRNA decay. Modulates the inflammatory response by promoting the degradation of a set of translationally active cytokine-induced inflammation-related mRNAs, such as IL6 and IL12B, during the early phase of inflammation. Prevents aberrant T-cell-mediated immune reaction by degradation of multiple mRNAs controlling T-cell activation, such as those encoding cytokines (IL6 and IL2), cell surface receptors (ICOS, TNFRSF4 and TNFR2) and transcription factor (REL). Inhibits cooperatively with ZC3H12A the differentiation of helper T cells Th17 in lungs. They repress target mRNA encoding the Th17 cell-promoting factors IL6, ICOS, REL, IRF4, NFKBID and NFKBIZ. The cooperation requires RNA-binding by RC3H1 and the nuclease activity of ZC3H12A. Together with RC3H1, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3’UTR. Self regulates by destabilizing its own mRNA. Cleaves mRNA harboring a stem-loop (SL), often located in their 3’-UTRs, during the early phase of inflammation in a helicase UPF1-dependent manner. Plays a role in the inhibition of microRNAs (miRNAs) biogenesis. Cleaves the terminal loop of a set of precursor miRNAs (pre-miRNAs) important for the regulation of the inflammatory response leading to their degradation, and thus preventing the biosynthesis of mature miRNAs. Also plays a role in promoting angiogenesis in response to inflammatory cytokines by inhibiting the production of antiangiogenic microRNAs via its anti-dicer RNase activity. Affects the overall ubiquitination of cellular proteins. Positively regulates deubiquitinase activity promoting the cleavage at ‘Lys-48’- and ‘Lys-63’-linked polyubiquitin chains on TNF receptor-associated factors (TRAFs), preventing JNK and NF-kappa-B signaling pathway activation, and hence negatively regulating macrophage-mediated inflammatory response and immune homeostasis. Also induces deubiquitination of the transcription factor HIF1A, probably leading to its stabilization and nuclear import, thereby positively regulating the expression of proangiogenic HIF1A-targeted genes. Involved in a TANK-dependent negative feedback response to attenuate NF-kappaB activation through the deubiquitination of IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage. Prevents stress granule (SGs) formation and promotes macrophage apoptosis under stress conditions, including arsenite-induced oxidative stress, heat shock and energy deprivation. Plays a role in the regulation of macrophage polarization; promotes IL4-induced polarization of macrophages M1 into anti-inflammatory M2 state. May also act as a transcription factor that regulates the expression of multiple genes involved in inflammatory response, angiogenesis, adipogenesis and apoptosis. Functions as a positive regulator of glial differentiation of neuroprogenitor cells through an amyloid precursor protein (APP)-dependent signaling pathway. Attenuates septic myocardial contractile dysfunction in response to lipopolysaccharide (LPS) by reducing I-kappa-B-kinase (IKK)-mediated NF-kappa-B activation, and hence myocardial pro-inflammatory cytokine production. (Microbial infection) Binds to Japanese encephalitis virus (JEV) and Dengue virus (DEN) RNAs. (Microbial infection) Exhibits antiviral activity against HIV-1 in lymphocytes by decreasing the abundance of HIV-1 viral RNA species.

Subunit / interactions. Oligomer. Found in a deubiquitination complex with TANK, USP10 and ZC3H12A; this complex inhibits genotoxic stress- or interleukin-1-beta-mediated NF-kappaB activation by promoting IKBKG or TRAF6 deubiquitination. Interacts with IKBKG; this interaction increases in response to DNA damage. Interacts with TANK; this interaction increases in response to DNA damage and serves as a bridge to anchor both TANK and USP10 into a deubiquitinating complex. Interacts with TRAF6; this interaction increases in response to DNA damage and is stimulated by TANK. Interacts with USP10; this interaction increases in response to DNA damage and serves as a bridge to anchor both TANK and USP10 into a deubiquitinating complex. Interacts with ZC3H12D. Interacts with TNRC6A. Interacts with IKBKB/IKKB. Interacts with IKBKB/IKKB. Interacts with BTRC; the interaction occurs when ZC3H12A is phosphorylated in a IKBKB/IKKB-dependent manner. Interacts with IRAK1; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB. Interacts with UPF1; this interaction occurs in a mRNA translationally active- and termination-dependent manner and is essential for ZC3H12A-mediated degradation of target mRNAs. Associates with ribosomes. Interacts with ubiquitin. (Microbial infection) Oligomerization is necessary for antiviral activity.

Subcellular location. Nucleus. Cytoplasm. P-body. Rough endoplasmic reticulum membrane. Cytoplasmic granule.

Tissue specificity. Expressed in heart, placenta, spleen, kidney, liver and lung. Expressed in leukocytes. Expressed in monocyte.

Post-translational modifications. Phosphorylated by IRAK1; phosphorylation is necessary for subsequent phosphorylation by the I-kappa-B-kinase (IKK) complex. Phosphorylated by I-kappa-B-kinase (IKK) subunits IKBKB/IKKB and CHUK/IKKA at Ser-438 and Ser-442; these phosphorylations promote ubiquitin proteasome-mediated degradation of ZC3H12A and hence facilitates rapid and robust production of IL-6 mRNA in response to toll-like receptor (TLR) or IL-1 receptor stimuli. (Microbial infection) Rapidly degraded in activated T-cells in response to phorbol 13-acetate 12-myristate (PMA) during HIV-1 viral infection. Ubiquitinated; ubiquitination is induced in response to interleukin IL1 receptor stimuli in a IKBKB/IKKB and IRAK1-dependent manner, leading to proteasome-mediated degradation. Proteolytically cleaved between Arg-111 and Arg-214 by MALT1 in activated T-cells; cleavage at Arg-111 is critical for promoting ZC3H12A degradation in response to T-cell receptor (TCR) stimulation, and hence is necessary for prolonging the stability of a set of mRNAs controlling T-cell activation and Th17 cell differentiation.

Disease relevance. Increased expression of ZC3H12A is associated with ischemic heart disease.

Cofactor. Mg(2+) is required for RNase activity.

Domain organisation. The C3H1-type zinc finger domain and C-terminal region are necessary for pre-miRNA binding. The C-terminal region and proline-rich domain are necessary for oligomerization. (Microbial infection) The C3H1-type zinc finger domain is necessary for JEV and DEN viral RNA-binding and antiviral activity.

Induction. Up-regulated by the transcription factor ELK1 in a interleukin IL1B-dependent manner through activation of the NF-kappa-B and ERK signaling pathways. Up-regulated by chemokine CCL2 in endothelial cells and in peripheral blood monocytes. Up-regulated in activated T lymphocytes. Up-regulated by phorbol 12-myristate 13-acetate (PMA) in primary T lymphocytes. Up-regulated by interleukin IL17 in keratinocytes. Up-regulated by lipopolysaccharide (LPS). Up-regulated by tumor necrosis factor TNF and interleukin IL1 in acute monocytic leukemia cell line THP-1 cells. Up-regulated by amyloid precursor protein (APP). (Microbial infection) Up-regulated in response to Japanese encephalitis virus (JEV) and dengue virus (DEN) infections.

Similarity. Belongs to the ZC3H12 family.

RefSeq proteins (3): NP_001310479, NP_001310480, NP_079355* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021869	RNase_Zc3h12_NYN	Domain
IPR040546	Rege-1_UBA-like	Domain
IPR040757	Regnase_1/ZC3H12_C	Domain
IPR051101	ZC3H12/N4BP1_RNase_Reg	Family

Pfam: PF11977, PF18039, PF18561

UniProt features (55 total): mutagenesis site 12, strand 10, region of interest 9, helix 8, modified residue 4, compositionally biased region 2, sequence variant 2, sequence conflict 2, turn 2, chain 1, domain 1, binding site 1, zinc finger region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3V32	X-RAY DIFFRACTION	2
3V34	X-RAY DIFFRACTION	2
3V33	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5D1E8-F1	67.37	0.36

Functional residue map

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

Ligand- & substrate-binding residues (1): 226

Post-translational modifications (4): 99, 344, 438, 442

Mutagenesis-validated functional residues (12):

Position	Phenotype
141	abolishes rnase activity.
141	loss of pre-mirna rnase activity. attenuates strongly mirna silencing activity. loss of interleukin il17a and il6 mrna i
144	no change in rnase activity.
157	does not inhibit antiviral effects.
214	abolishes rnase activity.
225	loss of pre-mirna rnase activity, il17a mrna instability and antiviral effects; when associated with a-226.
226	loss of pre-mirna rnase activity, il17a mrna instability and antiviral effects; when associated with a-225. loss of il1b
306	loss of interleukin il17a mrna instability. reduces weakly pre-mirna rnase activity. attenuates mirna silencing activity
311	inhibits transcriptional activity; when associated with g-312.
312	inhibits transcriptional activity; when associated with g-311.
317	inhibits transcriptional activity; when associated with g-318.
318	inhibits transcriptional activity; when associated with g-317.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9764302	Regulation of CDH19 Expression and Function

MSigDB gene sets: 572 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LIPID_STORAGE, GOBP_REGULATION_OF_AUTOPHAGY, GOMF_ENDONUCLEASE_ACTIVITY, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_CELLULAR_RESPONSE_TO_VIRUS, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT

GO Biological Process (57): negative regulation of transcription by RNA polymerase II (GO:0000122), nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184), angiogenesis (GO:0001525), negative regulation of protein phosphorylation (GO:0001933), positive regulation of defense response to virus by host (GO:0002230), immune response-activating signaling pathway (GO:0002757), apoptotic process (GO:0006915), inflammatory response (GO:0006954), DNA damage response (GO:0006974), nervous system development (GO:0007399), regulation of gene expression (GO:0010468), positive regulation of autophagy (GO:0010508), miRNA catabolic process (GO:0010587), positive regulation of endothelial cell migration (GO:0010595), positive regulation of gene expression (GO:0010628), negative regulation of muscle cell apoptotic process (GO:0010656), positive regulation of lipid storage (GO:0010884), protein deubiquitination (GO:0016579), cell differentiation (GO:0030154), negative regulation of type II interferon production (GO:0032689), negative regulation of interleukin-1 beta production (GO:0032691), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), cellular response to oxidative stress (GO:0034599), cellular response to glucose starvation (GO:0042149), positive regulation of protein import into nucleus (GO:0042307), negative regulation of macrophage activation (GO:0043031), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), host-mediated suppression of viral genome replication (GO:0044828), negative regulation of nitric oxide biosynthetic process (GO:0045019), positive regulation of fat cell differentiation (GO:0045600), positive regulation of angiogenesis (GO:0045766), positive regulation of transcription by RNA polymerase II (GO:0045944), T cell receptor signaling pathway (GO:0050852), protein complex oligomerization (GO:0051259), defense response to virus (GO:0051607), negative regulation of cardiac muscle contraction (GO:0055118), positive regulation of mRNA catabolic process (GO:0061014), 3’-UTR-mediated mRNA destabilization (GO:0061158), cellular response to lipopolysaccharide (GO:0071222)

GO Molecular Function (19): DNA binding (GO:0003677), chromatin binding (GO:0003682), RNA binding (GO:0003723), mRNA binding (GO:0003729), mRNA 3’-UTR binding (GO:0003730), RNA endonuclease activity (GO:0004521), RNA exonuclease activity (GO:0004532), RNA nuclease activity (GO:0004540), zinc ion binding (GO:0008270), miRNA binding (GO:0035198), RNA stem-loop binding (GO:0035613), mRNA 3’-UTR AU-rich region binding (GO:0035925), ribosome binding (GO:0043022), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), cysteine-type deubiquitinase activity (GO:0004843), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (11): P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), rough endoplasmic reticulum membrane (GO:0030867), protein-containing complex (GO:0032991), cytoplasmic ribonucleoprotein granule (GO:0036464), endoplasmic reticulum (GO:0005783), rough endoplasmic reticulum (GO:0005791), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of Expression and Function of Type II Classical Cadherins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
gene expression	2
nucleic acid binding	2
binding	2
RNA binding	2
RNA nuclease activity	2
nuclease activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
nuclear-transcribed mRNA catabolic process	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
regulation of protein phosphorylation	1
protein phosphorylation	1
negative regulation of protein modification process	1
negative regulation of phosphorylation	1
regulation of defense response to virus by host	1
activation of immune response	1
immune response-regulating signaling pathway	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
defense response	1
cellular response to stress	1
system development	1
regulation of macromolecule biosynthetic process	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
RNA catabolic process	1
miRNA metabolic process	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
muscle cell apoptotic process	1

Protein interactions and networks

STRING

1298 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZC3H12A	REG1B	P48304	905
ZC3H12A	REG1A	P05451	889
ZC3H12A	TANK	Q92844	889
ZC3H12A	RC3H1	Q5TC82	767
ZC3H12A	BFAR	Q9NZS9	762
ZC3H12A	CCL2	P13500	724
ZC3H12A	UPF1	Q92900	723
ZC3H12A	IL6	P05231	689
ZC3H12A	RC3H2	Q9HBD1	674
ZC3H12A	TRAF6	Q9Y4K3	660
ZC3H12A	ARID5A	Q03989	613
ZC3H12A	NFKBIZ	Q9BYH8	598
ZC3H12A	MALT1	Q9UDY8	576
ZC3H12A	ZFP36	P26651	560
ZC3H12A	CALCR	P30988	556

IntAct

45 interactions, top by confidence:

A	B	Type	Score
ZC3H12A	P4HA3	psi-mi:“MI:0915”(physical association)	0.720
P4HA3	ZC3H12A	psi-mi:“MI:0915”(physical association)	0.720
AHSP	ZC3H12A	psi-mi:“MI:0915”(physical association)	0.670
BTRC	ZC3H12A	psi-mi:“MI:0915”(physical association)	0.670
ZC3H12A	BTRC	psi-mi:“MI:0915”(physical association)	0.670
PRP2	ZC3H12A	psi-mi:“MI:0915”(physical association)	0.560
ZC3H12A	CAF40	psi-mi:“MI:0915”(physical association)	0.560
ZC3H12A	SKI8	psi-mi:“MI:0915”(physical association)	0.560
SKI8	ZC3H12A	psi-mi:“MI:0915”(physical association)	0.560
CAF40	ZC3H12A	psi-mi:“MI:0915”(physical association)	0.560
DNAJB13	ZC3H12A	psi-mi:“MI:0915”(physical association)	0.560
ZC3H12A	USP10	psi-mi:“MI:0914”(association)	0.560
USP10	ZC3H12A	psi-mi:“MI:0914”(association)	0.560
ZC3H12A	USP10	psi-mi:“MI:0915”(physical association)	0.560
USP10	ZC3H12A	psi-mi:“MI:0915”(physical association)	0.560
IKBKG	ZC3H12A	psi-mi:“MI:0915”(physical association)	0.520
ZC3H12A	SMAD3	psi-mi:“MI:0915”(physical association)	0.510
ZC3H12A	IRAK2	psi-mi:“MI:0915”(physical association)	0.500

BioGRID (69): ZC3H12A (Affinity Capture-Western), ZC3H12A (Two-hybrid), P4HA3 (Two-hybrid), ZC3H12A (Affinity Capture-Western), ZC3H12A (Two-hybrid), ZC3H12A (Two-hybrid), ZC3H12A (Affinity Capture-MS), ZC3H12A (Affinity Capture-RNA), IL1B (Affinity Capture-RNA), ZC3H12D (Affinity Capture-MS), ZC3H12D (Affinity Capture-Western), ZC3H12A (Affinity Capture-Western), ZC3H12D (Two-hybrid), ZC3H12A (Two-hybrid), ZC3H12A (Affinity Capture-Western)

ESM2 similar proteins: A0JPN4, A2A288, A2ARK0, A6ND36, A6QQJ8, A7E316, E9Q0S6, E9Q2Z1, O15037, O54714, O54967, O70260, O70405, O75385, O94983, P42335, P48778, Q07912, Q0P4K8, Q17R13, Q1LVK9, Q32PJ7, Q4V8I3, Q5D1E7, Q5D1E8, Q5DTV4, Q5HYM0, Q5JV73, Q5SWY7, Q5SXM2, Q5U2X5, Q5XIS1, Q68CZ2, Q6A037, Q6IRU7, Q6P1H6, Q6S5L8, Q7TP65, Q7TSG2, Q80U38

Diamond homologs: A0JPN4, A2A288, A6QQJ8, O15037, O75113, Q1LVK9, Q5D1E7, Q5D1E8, Q5DTV4, Q5DTZ0, Q5HYM0, Q5ZLE9, Q6A037, Q6DJS0, Q7ZXG4, Q80U38, Q8BIY3, Q95YE2, Q9C0D7, Q9P2P1, A6NKG5, Q8I7P9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ZC3H12A	“up-regulates quantity”	GATA2	“post transcriptional regulation”
ZC3H12A	“up-regulates quantity”	TAL1	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 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
canonical NF-kappaB signal transduction	5	101.8×	3e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	8
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1108 predictions. Top by Δscore:

Variant	Effect	Δscore
1:37475940:GTAA:G	donor_loss	1.0000
1:37480285:CCCA:C	acceptor_loss	1.0000
1:37480286:CCAG:C	acceptor_loss	1.0000
1:37480288:A:AG	acceptor_gain	1.0000
1:37480288:A:C	acceptor_loss	1.0000
1:37480289:G:GA	acceptor_gain	1.0000
1:37480289:GC:G	acceptor_gain	1.0000
1:37480289:GCC:G	acceptor_gain	1.0000
1:37480289:GCCA:G	acceptor_gain	1.0000
1:37480289:GCCAT:G	acceptor_gain	1.0000
1:37480430:G:C	donor_loss	1.0000
1:37480430:G:GG	donor_gain	1.0000
1:37481596:CCCA:C	acceptor_loss	1.0000
1:37481598:CA:C	acceptor_loss	1.0000
1:37481599:A:AG	acceptor_gain	1.0000
1:37481599:AGACC:A	acceptor_loss	1.0000
1:37481600:G:GT	acceptor_gain	1.0000
1:37481600:GACC:G	acceptor_gain	1.0000
1:37481600:GACCA:G	acceptor_gain	1.0000
1:37481831:GACAA:G	donor_gain	1.0000
1:37481832:ACAA:A	donor_gain	1.0000
1:37481833:CAA:C	donor_gain	1.0000
1:37481834:AA:A	donor_gain	1.0000
1:37481836:G:GG	donor_gain	1.0000
1:37481836:GTAT:G	donor_loss	1.0000
1:37481837:T:A	donor_loss	1.0000
1:37482204:G:GT	donor_gain	1.0000
1:37482521:G:GT	donor_gain	1.0000
1:37482539:TGGT:T	donor_loss	1.0000
1:37482541:G:GA	donor_loss	1.0000

AlphaMissense

3858 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:37475912:T:A	V139D	1.000
1:37475918:A:T	D141V	1.000
1:37475920:G:T	G142W	1.000
1:37475921:G:A	G142E	1.000
1:37475928:C:A	N144K	1.000
1:37475928:C:G	N144K	1.000
1:37480309:T:C	F155L	1.000
1:37480311:C:A	F155L	1.000
1:37480311:C:G	F155L	1.000
1:37480317:C:G	C157W	1.000
1:37480321:G:C	G159R	1.000
1:37480385:C:A	P180Q	1.000
1:37480390:T:A	W182R	1.000
1:37480390:T:C	W182R	1.000
1:37480394:G:C	R183T	1.000
1:37480395:G:C	R183S	1.000
1:37480395:G:T	R183S	1.000
1:37481684:T:C	C223R	1.000
1:37481685:G:A	C223Y	1.000
1:37481686:C:G	C223W	1.000
1:37481690:G:C	D225H	1.000
1:37481691:A:C	D225A	1.000
1:37481691:A:T	D225V	1.000
1:37481693:G:C	D226H	1.000
1:37481694:A:C	D226A	1.000
1:37481694:A:G	D226G	1.000
1:37481694:A:T	D226V	1.000
1:37481695:C:A	D226E	1.000
1:37481695:C:G	D226E	1.000
1:37481699:T:C	F228L	1.000

dbSNP variants (sampled 300 via entrez): RS1000033213 (1:37474159 C>G,T), RS1000380123 (1:37483876 C>G), RS1000490301 (1:37477676 A>G), RS1000563166 (1:37479065 C>A), RS1000635299 (1:37478835 A>T), RS1000692095 (1:37484466 C>A,T), RS1000933252 (1:37473501 C>G), RS1001147078 (1:37484594 T>C), RS1001371042 (1:37479622 G>A), RS1001426653 (1:37479852 G>A), RS1001581049 (1:37477133 C>A), RS1001688916 (1:37473686 T>C), RS1001861567 (1:37484239 CAG>C), RS1002315492 (1:37484433 G>A), RS1002348431 (1:37472667 A>T)

Disease associations

OMIM: gene MIM:610562 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003476_2	Eyebrow thickness	7.000000e-06
GCST90002390_594	Mean corpuscular hemoglobin	4.000000e-31
GCST90002404_459	Red cell distribution width	7.000000e-18

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Silicon Dioxide	decreases reaction, increases expression, decreases methylation	3
Lipopolysaccharides	affects response to substance, affects cotreatment, increases expression	2
Nickel	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
Glupearl 19S	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
titanium dioxide	decreases methylation	1
2-methyl-4-isothiazolin-3-one	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, affects response to substance, increases expression	1
celastrol	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
gedunin	decreases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, increases expression	1
licochalcone B	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
RS 102895	decreases reaction, increases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TY56	HAP1 ZC3H12A (-) 1	Cancer cell line	Male
CVCL_XV25	HAP1 ZC3H12A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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