Affinage

MDFIC

MyoD family inhibitor domain-containing protein · UniProt Q9P1T7

Length
246 aa
Mass
25.8 kDa
Annotated
2026-06-10
100 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MDFIC is a MyoD family inhibitor domain-containing protein with roles spanning lymphatic vascular morphogenesis, transcriptional control of tumor suppression, and myogenic cell behavior (PMID:35235341, PMID:32457453, PMID:31261950). Its best-defined function is in lymphatic development: biallelic loss-of-function variants cause central conducting lymphatic anomaly with chylothorax and lymphedema in humans, and a mouse truncation knock-in recapitulates perinatal lethality with mispatterned lymphatic vasculature and defective valve formation; mechanistically MDFIC governs collective endothelial cell migration during valve morphogenesis by regulating integrin β1 activation and lymphatic endothelial cell–extracellular matrix interaction (PMID:35235341). In a transcriptional role, MDFIC physically associates with the histone demethylase JMJD1A and stimulates transcription of the HIC1 tumor suppressor, an axis that suppresses growth of colorectal cancer cells (PMID:32457453). Independent work places MDFIC as a positive regulator of myoblast proliferation, survival, and differentiation downstream of the PI3K/AKT pathway, with its expression controlled by targeting miRNAs (PMID:31261950). How these distinct activities are unified at the molecular level has not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1995 Medium

    Established the HIC-1/MDFIC locus as a p53-responsive candidate tumor suppressor, linking it to growth control via a defined regulatory input.

    Evidence p53 co-transfection reporter assays and colony suppression in brain, breast, and colon cancer lines

    PMID:7585125

    Open questions at the time
    • Did not define the protein's molecular activity or partners
    • Colony suppression mechanism not resolved at the pathway level
  2. 2006 Low

    Tested whether MDFIC is inactivated by point mutation in myeloid neoplasms with chromosome 7 loss, showing loss occurs by deletion rather than coding mutation.

    Evidence Microsatellite mapping and coding-region mutation screening in 15 patients with chromosome 7 deletions

    PMID:17064770

    Open questions at the time
    • Negative mutation result; haploinsufficiency role not functionally demonstrated
    • Small patient cohort, single method
  3. 2016 Low

    Identified post-transcriptional control of MDFIC by a miRNA and a link to transformed lymphoid cell proliferation, beginning to place MDFIC in proliferation regulation.

    Evidence Dual luciferase reporter, western blot, and proliferation assays for gga-miR-130a targeting chicken MDFIC

    PMID:27178573

    Open questions at the time
    • Single lab, chicken ortholog; downstream pathway mechanism not defined
    • Direct molecular function of MDFIC not addressed
  4. 2019 Medium

    Placed MDFIC as a positive regulator of myoblast proliferation, survival, and differentiation through the PI3K/AKT pathway, and confirmed miRNA-mediated repression.

    Evidence miR-146b-3p luciferase target validation plus siRNA knockdown with proliferation, differentiation, and apoptosis assays in chicken myoblasts

    PMID:31261950

    Open questions at the time
    • Mechanistic connection from MDFIC to PI3K/AKT not defined
    • Chicken ortholog context; human relevance not directly tested
  5. 2020 Medium

    Defined a transcriptional mechanism for MDFIC tumor suppression by linking it physically to JMJD1A and functionally to HIC1 activation.

    Evidence Co-immunoprecipitation with JMJD1A and overexpression/knockdown growth and gene-expression assays in HCT116 colorectal cancer cells

    PMID:32457453

    Open questions at the time
    • Single Co-IP without structural or reciprocal partner mapping
    • Direct DNA-binding versus cofactor role at the HIC1 promoter not resolved
  6. 2022 High

    Established MDFIC as a disease gene for central conducting lymphatic anomaly and defined its cellular mechanism in lymphatic valve morphogenesis.

    Evidence Human biallelic-variant mapping in 7 individuals, mouse truncation knock-in, and integrin β1 activation and cell-ECM interaction assays

    PMID:35235341

    Open questions at the time
    • Direct molecular link between MDFIC and integrin β1 activation not biochemically resolved
    • How MDFIC's transcriptional and lymphatic functions relate is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The unifying molecular activity of MDFIC that connects its lymphatic-developmental, transcriptional, and myogenic roles remains undefined.
  • No structural model or defined enzymatic/binding activity in the corpus
  • Whether one molecular function underlies all reported phenotypes is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 1
Pathway
R-HSA-1266738 Developmental Biology 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
JMJD1A

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 HIC-1 (MDFIC alias context: this paper is about HIC-1/MDFIC locus at 17p13.3) is transcriptionally activated by wild-type p53 via a p53 binding site in its 5' flanking region, and forced expression of HIC-1 suppresses G418 selectability (colony formation) of brain, breast, and colon cancer cells, establishing it as a p53-regulated candidate tumor suppressor. Reporter/expression assays with wild-type p53 transfection; colony suppression assay in cancer cell lines Nature medicine Medium 7585125
2006 The HIC gene (MDFIC; alias MyoD family inhibitor domain containing) maps to chromosome 7q31.1 within a minimal region of loss in myeloid neoplasms, but mutation screening of the coding region and intron-exon boundaries in 15 patients with chromosome 7 deletions found no mutations in MDFIC, suggesting loss of function occurs by deletion rather than point mutation. Microsatellite mapping; mutation screening by sequencing of coding regions Leukemia research Low 17064770
2020 MDFIC interacts with the histone demethylase JMJD1A, inhibits growth of HCT116 colorectal cancer cells, and stimulates transcription of the HIC1 tumor suppressor gene; MDFIC overexpression phenocopies HIC1-mediated growth suppression, defining a MDFIC→HIC1 tumor-suppressive axis in colorectal cancer. Co-immunoprecipitation (interaction with JMJD1A); cell growth assays (overexpression/knockdown); gene expression analysis Scientific reports Medium 32457453
2022 Biallelic pathogenic variants in MDFIC cause central conducting lymphatic anomaly (CCLA) with chylothorax and lymphedema in humans and mice. In a mouse model of human MDFIC truncation variants, homozygous mutants die perinatally with chylothorax and profoundly mispatterned lymphatic vasculature with major defects in lymphatic vessel valve development. Mechanistically, MDFIC controls collective cell migration during lymphatic valve formation by regulating integrin β1 activation and the interaction between lymphatic endothelial cells and their extracellular matrix. Human genetic mapping (biallelic variants in 7 individuals); mouse truncation knock-in model (perinatal lethality, lymphatic patterning defects); integrin β1 activation assays; cell-ECM interaction assays Science translational medicine High 35235341
2019 miR-146b-3p directly targets MDFIC (confirmed by dual luciferase reporter assay), and MDFIC knockdown suppresses proliferation and differentiation while promoting apoptosis of chicken myoblasts, indicating MDFIC promotes myoblast proliferation and survival via the PI3K/AKT pathway. Dual luciferase reporter assay (miRNA target validation); siRNA knockdown; proliferation, differentiation, and apoptosis assays in chicken myoblasts Cells Medium 31261950
2016 gga-miR-130a directly targets MDFIC (chicken ortholog) as confirmed by dual luciferase reporter assay and western blot (protein but not mRNA level regulation), and both MDFIC and HOXA3 are involved in regulating MDV-transformed lymphoid cell proliferation. Dual luciferase reporter assay; western blot; qRT-PCR; proliferation and migration assays Molecular biology reports Low 27178573

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 YaHS: yet another Hi-C scaffolding tool. Bioinformatics (Oxford, England) 1422 36525368
2013 Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature 1181 24067610
2012 Hi-C: a comprehensive technique to capture the conformation of genomes. Methods (San Diego, Calif.) 899 22652625
2017 3D structures of individual mammalian genomes studied by single-cell Hi-C. Nature 619 28289288
2019 Integrating Hi-C links with assembly graphs for chromosome-scale assembly. PLoS computational biology 542 31433799
2017 Massively multiplex single-cell Hi-C. Nature methods 436 28135255
1995 p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nature medicine 394 7585125
2010 Hi-C: a method to study the three-dimensional architecture of genomes. Journal of visualized experiments : JoVE 364 20461051
2015 Condensin- and Replication-Mediated Bacterial Chromosome Folding and Origin Condensation Revealed by Hi-C and Super-resolution Imaging. Molecular cell 218 26295962
2024 Cooltools: Enabling high-resolution Hi-C analysis in Python. PLoS computational biology 215 38709825
2020 Coolpup.py: versatile pile-up analysis of Hi-C data. Bioinformatics (Oxford, England) 161 32003791
2015 An Overview of Genome Organization and How We Got There: from FISH to Hi-C. Microbiology and molecular biology reviews : MMBR 151 26223848
2011 Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis. Molecular biology of the cell 148 21148292
2021 Multiscale and integrative single-cell Hi-C analysis with Higashi. Nature biotechnology 142 34635838
2023 Linking genome structures to functions by simultaneous single-cell Hi-C and RNA-seq. Science (New York, N.Y.) 124 37289875
2019 Measuring the reproducibility and quality of Hi-C data. Genome biology 121 30890172
2019 Revealing Hi-C subcompartments by imputing inter-chromosomal chromatin interactions. Nature communications 119 31699985
2018 Genome-wide Hi-C analysis reveals extensive hierarchical chromatin interactions in rice. The Plant journal : for cell and molecular biology 111 29660196
2024 Chromosome-level scaffolding of haplotype-resolved assemblies using Hi-C data without reference genomes. Nature plants 100 39103456
1999 DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. Hepatology (Baltimore, Md.) 93 10051471
2020 Hi-C Identifies Complex Genomic Rearrangements and TAD-Shuffling in Developmental Diseases. American journal of human genetics 92 32470376
2007 Hic-5 contributes to epithelial-mesenchymal transformation through a RhoA/ROCK-dependent pathway. Journal of cellular physiology 89 17299801
2005 Hic-5 regulates an epithelial program mediated by PPARgamma. Genes & development 89 15687259
2018 Principles of Chromosome Architecture Revealed by Hi-C. Trends in biochemical sciences 86 29685368
2001 Hic-5-reduced cell spreading on fibronectin: competitive effects between paxillin and Hic-5 through interaction with focal adhesion kinase. Molecular and cellular biology 85 11463817
2021 Hi-C 3.0: Improved Protocol for Genome-Wide Chromosome Conformation Capture. Current protocols 84 34286910
1998 Interaction of Hic-5, A senescence-related protein, with focal adhesion kinase. The Journal of biological chemistry 80 9756887
2018 MEF2 and the tumorigenic process, hic sunt leones. Biochimica et biophysica acta. Reviews on cancer 69 29879430
2018 Hi-C analysis: from data generation to integration. Biophysical reviews 66 30570701
2009 The progesterone receptor coactivator Hic-5 is involved in the pathophysiology of endometriosis. Endocrinology 64 19389829
2017 HiC-bench: comprehensive and reproducible Hi-C data analysis designed for parameter exploration and benchmarking. BMC genomics 61 28056762
2022 dcHiC detects differential compartments across multiple Hi-C datasets. Nature communications 58 36369226
2019 Deciphering Hi-C: from 3D genome to function. Cell biology and toxicology 57 30610495
2004 A LIM protein, Hic-5, functions as a potential coactivator for Sp1. Journal of cellular biochemistry 56 14755691
2023 Hi-C metagenome sequencing reveals soil phage-host interactions. Nature communications 55 37996432
2012 Paxillin and Hic-5 interaction with vinculin is differentially regulated by Rac1 and RhoA. PloS one 55 22629471
2021 High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis. Journal of hematology & oncology 53 34348759
2017 HUGIn: Hi-C Unifying Genomic Interrogator. Bioinformatics (Oxford, England) 51 28582503
2001 Identification and characterization of hic-5/ARA55 as an hsp27 binding protein. The Journal of biological chemistry 50 11546764
2022 Loop detection using Hi-C data with HiCExplorer. GigaScience 48 35809047
2016 Hic-5 remodeling of the stromal matrix promotes breast tumor progression. Oncogene 48 27893716
2003 Expression of the LIM proteins paxillin and Hic-5 in human tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 47 12642630
2003 Epigenetic silencing of the HIC-1 gene in human medulloblastomas. Journal of neuropathology and experimental neurology 47 14656076
2023 Epiphany: predicting Hi-C contact maps from 1D epigenomic signals. Genome biology 46 37280678
2017 Software tools for visualizing Hi-C data. Genome biology 46 28159004
2024 Droplet Hi-C enables scalable, single-cell profiling of chromatin architecture in heterogeneous tissues. Nature biotechnology 44 39424717
2004 Analysis of HIC-1 methylation and transcription in human ependymomas. International journal of cancer 44 15122586
2018 Unsupervised embedding of single-cell Hi-C data. Bioinformatics (Oxford, England) 43 29950005
2021 HiC-DC+ enables systematic 3D interaction calls and differential analysis for Hi-C and HiChIP. Nature communications 42 34099725
2021 Single-cell Hi-C data analysis: safety in numbers. Briefings in bioinformatics 40 34406348
2019 The Inhibition on MDFIC and PI3K/AKT Pathway Caused by miR-146b-3p Triggers Suppression of Myoblast Proliferation and Differentiation and Promotion of Apoptosis. Cells 38 31261950
2001 Expression of the Hypermethylated in Cancer gene (HIC-1) is associated with good outcome in human breast cancer. British journal of cancer 36 11747329
2022 Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema. Science translational medicine 35 35235341
2021 HiCRep.py: fast comparison of Hi-C contact matrices in Python. Bioinformatics (Oxford, England) 33 33576390
2010 Epithelial Hic-5/ARA55 expression contributes to prostate tumorigenesis and castrate responsiveness. Oncogene 33 20818421
2014 Hic-5 influences genomic and non-genomic actions of the androgen receptor in prostate myofibroblasts. Molecular and cellular endocrinology 31 24440747
2011 Promoter hypermethylation of RASSF1A, MGMT, and HIC-1 genes in benign and malignant colorectal tumors. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 31 21274674
2002 Transcriptional activation of the c-fos gene by a LIM protein, Hic-5. Biochemical and biophysical research communications 31 12445807
2019 HIC-5 in cancer-associated fibroblasts contributes to esophageal squamous cell carcinoma progression. Cell death & disease 30 31740661
2018 Practical Analysis of Hi-C Data: Generating A/B Compartment Profiles. Methods in molecular biology (Clifton, N.J.) 29 30218370
2007 Hic-5 promotes endothelial cell migration to lysophosphatidic acid. American journal of physiology. Heart and circulatory physiology 27 17337598
2015 Hic-5 Regulates Actin Cytoskeletal Reorganization and Expression of Fibrogenic Markers and Myocilin in Trabecular Meshwork Cells. Investigative ophthalmology & visual science 26 26313302
2006 HIC gene, a candidate suppressor gene within a minimal region of loss at 7q31.1 in myeloid neoplasms. Leukemia research 24 17064770
2020 Opposite Roles of the JMJD1A Interaction Partners MDFI and MDFIC in Colorectal Cancer. Scientific reports 23 32457453
2018 Iteratively improving Hi-C experiments one step at a time. Methods (San Diego, Calif.) 22 29723572
2023 Single cell Hi-C identifies plastic chromosome conformations underlying the gastrulation enhancer landscape. Nature communications 21 37386027
2021 Chrom-Lasso: a lasso regression-based model to detect functional interactions using Hi-C data. Briefings in bioinformatics 21 34013331
2019 Chromosome genome assembly and annotation of the yellowbelly pufferfish with PacBio and Hi-C sequencing data. Scientific data 21 31704938
2006 Hic-5/ARA55: a prostate stroma-specific AR coactivator. Steroids 21 17166536
2021 A cookbook for DNase Hi-C. Epigenetics & chromatin 20 33743768
2021 3D disorganization and rearrangement of genome provide insights into pathogenesis of NAFLD by integrated Hi-C, Nanopore, and RNA sequencing. Acta pharmaceutica Sinica. B 20 34729306
2016 Hic-5 mediates the initiation of endothelial sprouting by regulating a key surface metalloproteinase. Journal of cell science 19 26769900
2015 Hi-C in Budding Yeast. Cold Spring Harbor protocols 19 26134906
2024 Hi-C techniques: from genome assemblies to transcription regulation. Journal of experimental botany 18 38430521
2023 A Comparison of Topologically Associating Domain Callers Based on Hi-C Data. IEEE/ACM transactions on computational biology and bioinformatics 18 35104223
2022 HiCARN: resolution enhancement of Hi-C data using cascading residual networks. Bioinformatics (Oxford, England) 18 35274679
2022 Every gene everywhere all at once: High-precision measurement of 3D chromosome architecture with single-cell Hi-C. Frontiers in molecular biosciences 18 36275628
2019 Identification of recurrent noncoding mutations in B-cell lymphoma using capture Hi-C. Blood advances 18 30606723
2019 The focal adhesion scaffold protein Hic-5 regulates vimentin organization in fibroblasts. Molecular biology of the cell 18 31644368
2021 Identifying high-confidence capture Hi-C interactions using CHiCANE. Nature protocols 17 33837305
2019 Hi-C detects novel structural variants in HL-60 and HL-60/S4 cell lines. Genomics 16 31095996
2016 Chicken gga-miR-130a targets HOXA3 and MDFIC and inhibits Marek's disease lymphoma cell proliferation and migration. Molecular biology reports 16 27178573
2023 Deep generative modeling and clustering of single cell Hi-C data. Briefings in bioinformatics 15 36458445
2024 Removing unwanted variation between samples in Hi-C experiments. Briefings in bioinformatics 14 38711367
2021 Extracting multi-way chromatin contacts from Hi-C data. PLoS computational biology 14 34871311
2018 Three invariant Hi-C interaction patterns: Applications to genome assembly. Methods (San Diego, Calif.) 14 29684640
2023 Low input capture Hi-C (liCHi-C) identifies promoter-enhancer interactions at high-resolution. Nature communications 13 36650138
2021 Hi-C as a molecular rangefinder to examine genomic rearrangements. Seminars in cell & developmental biology 13 33992531
2023 Integrative Identification by Hi-C Revealed Distinct Advanced Structural Variations in Lung Adenocarcinoma Tissue. Phenomics (Cham, Switzerland) 12 37589026
2023 The shape of chromatin: insights from computational recognition of geometric patterns in Hi-C data. Briefings in bioinformatics 12 37646128
2023 Tracing cancer evolution and heterogeneity using Hi-C. Nature communications 12 37932252
2021 Chromosome Modeling on Downsampled Hi-C Maps Enhances the Compartmentalization Signal. The journal of physical chemistry. B 12 34319725
2021 Molecular interaction of HIC, an agonist of P2Y1 receptor, and its role in prostate cancer apoptosis. International journal of biological macromolecules 12 34425116
2022 A review and performance evaluation of clustering frameworks for single-cell Hi-C data. Briefings in bioinformatics 11 36151714
2021 Seeing the forest through the trees: prioritising potentially functional interactions from Hi-C. Epigenetics & chromatin 11 34454581
2019 Methods for comparative ChIA-PET and Hi-C data analysis. Methods (San Diego, Calif.) 11 31629084
2024 Hi-BDiSCO: folding 3D mesoscale genome structures from Hi-C data using brownian dynamics. Nucleic acids research 10 38015443
2023 Chromosome-level assembly of Dictyophora rubrovolvata genome using third-generation DNA sequencing and Hi-C analysis. G3 (Bethesda, Md.) 10 37178144
2023 Single-cell Hi-C data enhancement with deep residual and generative adversarial networks. Bioinformatics (Oxford, England) 10 37498561
2023 Subgraph extraction and graph representation learning for single cell Hi-C imputation and clustering. Briefings in bioinformatics 10 38040494

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