Affinage

ZC3H10

Zinc finger CCCH domain-containing protein 10 · UniProt Q96K80

Length
434 aa
Mass
46.1 kDa
Annotated
2026-04-28
16 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZC3H10 is a CCCH-type zinc finger transcription factor that drives thermogenic and metabolic gene programs and promotes mitochondrial function during differentiation of adipocytes and myoblasts. ZC3H10 binds the distal promoter of UCP1, and upon p38 MAPK-mediated phosphorylation at S126, it recruits the H3K79 methyltransferase Dot1l to activate thermogenic gene transcription in brown adipose tissue (PMID:31775033, PMID:33107819). Beyond thermogenesis, ZC3H10 is required for mitochondrial biogenesis and electron transport chain subunit expression, and its depletion impairs TCA cycle flux and oxygen consumption (PMID:29507079). During early adipogenesis, ZC3H10 represses excess protein translation and promotes F-actin remodeling and mitochondrial function, thereby enabling differentiation into mature adipocytes (PMID:33566069).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2008 Medium

    Before any metabolic role was recognized, ZC3H10 was first linked to TNFα signaling and growth suppression, establishing it as a functionally relevant gene in proliferation control.

    Evidence Gene trap screen in MCF-7 cells identified ZC3H10 as TNFα-regulated; soft agar assays showed inhibition of anchorage-independent growth

    PMID:18814840

    Open questions at the time
    • No mechanistic follow-up on how ZC3H10 inhibits colony formation
    • No link to transcription factor activity or metabolic roles at this stage
  2. 2018 High

    A genome-wide screen established ZC3H10 as a mitochondrial regulator, showing for the first time that it controls ETC subunit expression and TCA cycle flux, and that its loss blocks myoblast differentiation.

    Evidence Functional genomic screen with overexpression and siRNA knockdown in myoblasts, oxygen consumption measurement, metabolomics, ETC subunit expression analysis

    PMID:29507079

    Open questions at the time
    • Direct transcriptional targets of ZC3H10 at ETC/TCA loci not mapped
    • Mechanism by which ZC3H10 activates mitochondrial gene expression unknown
  3. 2019 High

    The molecular mechanism in thermogenesis was resolved: ZC3H10 acts as a transcription factor binding the far-upstream UCP1 promoter, and p38 MAPK phosphorylation at S126 enhances this binding upon sympathetic stimulation, answering how ZC3H10 is signal-regulated.

    Evidence ChIP, reporter assays, S126 phospho-site mutagenesis, p38 MAPK inhibition, adipose-specific Zc3h10 KO (UCP1-Cre) with thermogenic and oxygen consumption phenotyping in vivo

    PMID:31775033

    Open questions at the time
    • Genome-wide binding profile of ZC3H10 not determined
    • Whether ZC3H10 DNA binding is zinc-finger-dependent or involves RNA intermediates was not fully resolved
  4. 2020 High

    The coactivator mechanism was identified: Dot1l directly interacts with ZC3H10 and is recruited to thermogenic gene promoters where it methylates H3K79, establishing the chromatin-modifying step downstream of ZC3H10 binding.

    Evidence Reciprocal co-immunoprecipitation, ChIP for H3K79me, Dot1l KO mice (UCP1-Cre) with thermogenic and energy expenditure measurements

    PMID:33107819

    Open questions at the time
    • Structural basis of ZC3H10–Dot1l interaction unknown
    • Whether additional chromatin remodelers cooperate with ZC3H10 not tested
  5. 2021 High

    ZC3H10's role was extended beyond thermogenesis to general adipogenesis, revealing that it represses protein translation and promotes F-actin remodeling — two processes prerequisite for mitochondrial function and adipocyte maturation.

    Evidence siRNA knockdown and overexpression in preadipocytes, polysome profiling, F-actin staining, mitochondrial function assays, metabolomics, differentiation assays

    PMID:33566069

    Open questions at the time
    • Direct transcriptional targets mediating translational repression and actin remodeling not identified
    • Whether the translation-repressive function uses ZC3H10's RNA-binding zinc fingers is untested
  6. 2022 Medium

    Cross-species validation in bovine cells confirmed ZC3H10's role in thermogenic and metabolic gene regulation under cold stress, and extended its target repertoire to lipid transport genes PLTP and APOA1.

    Evidence CRISPR/Cas9 knockout of ZC3H10 in bovine fetal fibroblasts with RNA-seq at two temperatures

    PMID:36292795

    Open questions at the time
    • PLTP and APOA1 regulation not confirmed as direct transcriptional targets
    • Functional rescue not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the genome-wide direct target repertoire of ZC3H10, the structural basis of its interaction with Dot1l, whether its zinc finger domain contributes to RNA binding in vivo, and how its translational repression and cytoskeletal remodeling functions are mechanistically executed.
  • No ChIP-seq or CUT&RUN map of ZC3H10 binding sites
  • No structural data for ZC3H10 or ZC3H10–Dot1l complex
  • RNA-binding function in adipogenesis context not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1430728 Metabolism 3 GO:0005739 mitochondrion 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-162582 Signal Transduction 1
Partners
DOT1LMAPK14

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Zc3h10 was identified as a novel regulator of mitochondrial physiology through a genome-wide functional screen. Zc3h10 overexpression boosts mitochondrial function and promotes myoblast differentiation, while its depletion results in impaired myoblast differentiation, mitochondrial dysfunction, reduced expression of electron transport chain (ETC) subunits, and blunted TCA cycle flux. Genome-wide functional screen, overexpression and siRNA knockdown with oxygen consumption rate measurement, metabolomics, and ETC subunit expression analysis EMBO reports High 29507079
2019 Zc3h10 functions as a transcription factor that activates UCP1 by binding to a far upstream region of the UCP1 promoter (not the enhancer). Upon sympathetic stimulation, Zc3h10 is phosphorylated at S126 by p38 MAPK, which increases its binding to the distal region of the UCP1 promoter to activate the thermogenic gene program. ChIP assay, reporter assays, phosphorylation site mutagenesis (S126), p38 MAPK inhibition, RNA-binding mutant analysis, in vivo adipose-specific Zc3h10 ablation (UCP1-Cre) with thermogenic capacity and oxygen consumption measurements Cell reports High 31775033
2020 Dot1l (the only known H3K79 methyltransferase) directly interacts with Zc3h10 and is recruited by Zc3h10 to the promoter regions of thermogenic genes (including UCP1), where it methylates H3K79 to function as a coactivator of the thermogenic gene program. Co-immunoprecipitation (direct interaction), ChIP assay, H3K79 methylation analysis, Dot1l KO mice (UCP1-Cre) with thermogenic capacity and energy expenditure measurements eLife High 33107819
2021 Zc3h10 acts as a critical proadipogenic transcription factor in early adipogenesis: its depletion in preadipocytes causes increased protein translation and impaired filamentous (F)-actin remodeling, leading to mitochondrial and metabolic dysfunction that blocks differentiation into mature adipocytes. Conversely, Zc3h10 overexpression promotes adipocyte maturation with increased lipid droplet size. siRNA knockdown, overexpression, polysome profiling (translation measurement), F-actin staining, mitochondrial function assays, metabolomics, adipocyte differentiation assays The Journal of cell biology High 33566069
2008 ZC3H10 was identified as a TNFα-regulated gene via a gene trap screen in MCF-7 cells, and ZC3H10 inhibits anchorage-independent growth in soft agar, suggesting a tumor suppressor function. Gene trap screen, soft agar colony formation assay Biochemical and biophysical research communications Medium 18814840
2022 CRISPR/Cas9 knockout of ZC3H10 in bovine fetal fibroblast cells dysregulated pathways involved in thermogenesis and immunity under cold stress, and ZC3H10 was shown to regulate genes involved in glucose and lipid metabolism and lipid transport (PLTP and APOA1), facilitating cold stress adaptation. CRISPR/Cas9 knockout, transcriptomic analysis (RNA-seq) at two temperature conditions, pathway analysis Genes Medium 36292795
2020 ZC3H10 is a target gene repressed by a HOTAIR regulatory element; deletion of this regulatory element increases glioma cell sensitivity to temozolomide and de-represses ZC3H10 transcription, with rescue experiments and 3C data confirming that ZC3H10 function contributes to regulating glioma cell TMZ sensitivity. CRISPR/Cas9 regulatory element deletion, RNA-seq, Capture Hi-C, 3C, rescue experiments Genome research Medium 31953347

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis. Molecular cell 247 28431233
2018 Transcriptome analysis of adipose tissues from two fat-tailed sheep breeds reveals key genes involved in fat deposition. BMC genomics 83 29739312
2020 A HOTAIR regulatory element modulates glioma cell sensitivity to temozolomide through long-range regulation of multiple target genes. Genome research 36 31953347
2021 Zc3h10 regulates adipogenesis by controlling translation and F-actin/mitochondria interaction. The Journal of cell biology 27 33566069
2018 Zc3h10 is a novel mitochondrial regulator. EMBO reports 27 29507079
2019 Zc3h10 Acts as a Transcription Factor and Is Phosphorylated to Activate the Thermogenic Program. Cell reports 21 31775033
2008 Gene trapping identifies a putative tumor suppressor and a new inducer of cell migration. Biochemical and biophysical research communications 21 18814840
2020 Epigenetic dynamics of the thermogenic gene program of adipocytes. The Biochemical journal 20 32219439
2023 Pan-primate studies of age and sex. GeroScience 19 37493860
2020 Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes. eLife 15 33107819
2018 A Novel 12q13.2-q13.3 Microdeletion Syndrome With Combined Features of Diamond Blackfan Anemia, Pierre Robin Sequence and Klippel Feil Deformity. Frontiers in genetics 14 30524470
2023 Genome-Wide Association Analysis Identifies the PMEL Gene Affecting Coat Color and Birth Weight in Simmental × Holstein. Animals : an open access journal from MDPI 12 38136858
2022 Assessment of a zinc finger protein gene (MPZC3H10) as potential RNAi target for green peach aphid Myzus persicae control. Pest management science 9 36181420
2022 Identification of Circular RNA-Based Immunomodulatory Networks in Colorectal Cancer. Frontiers in oncology 6 35155186
2022 Selection Signature and CRISPR/Cas9-Mediated Gene Knockout Analyses Reveal ZC3H10 Involved in Cold Adaptation in Chinese Native Cattle. Genes 6 36292795
2021 Selection of a reference gene for studies on lipid-related aquatic adaptations of toothed whales (Grampus griseus). Ecology and evolution 2 34938499