MACMIC Reveals A Dual Role of CTCF in Epigenetic Regulation of Cell Identity Genes

Numerous studies of relationship between epigenomic features have focused on their strong correlation across the genome, likely because such relationship can be easily identified by many established methods for correlation analysis. However, two features with little correlation may still colocalize at many genomic sites to implement important functions. There is no bioinformatic tool for researchers to specifically identify such feature pairs. Here, we develop a method to identify feature pairs in which two features have maximal colocalization minimal correlation (MACMIC) across the genome. By MACMIC analysis of 3306 feature pairs in 16 human cell types, we reveal a dual role of CCCTC-binding factor (CTCF) in epigenetic regulation of cell identity genes. Although super-enhancers are associated with activation of target genes, only a subset of super-enhancers colocalized with CTCF regulate cell identity genes. At super-enhancers colocalized with CTCF, CTCF is required for the active marker H3K27ac in cell types requiring the activation, and also required for the repressive marker H3K27me3 in other cell types requiring repression. Our work demonstrates the biological utility of the MACMIC analysis and reveals a key role for CTCF in epigenetic regulation of cell identity. The code for MACMIC is available at https://github.com/bxia888/MACMIC.

[1]  V. Corces,et al.  CTCF: Master Weaver of the Genome , 2009, Cell.

[2]  Neva C. Durand,et al.  Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes , 2015, Proceedings of the National Academy of Sciences.

[3]  A. Schier,et al.  Bivalent histone modifications in early embryogenesis. , 2012, Current opinion in cell biology.

[4]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[5]  M. Kaplan,et al.  Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation. , 2017, Molecular cell.

[6]  Wen Jin,et al.  Predicting gene expression level by the transcription factor binding signals in human embryonic stem cells , 2016, Biosyst..

[7]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[8]  Marius Wernig,et al.  Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells , 2012, Proceedings of the National Academy of Sciences.

[9]  N. Galjart,et al.  CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart , 2017, PLoS Genetics.

[10]  A. Hoffman,et al.  CTCF Regulates Allelic Expression of Igf2 by Orchestrating a Promoter-Polycomb Repressive Complex 2 Intrachromosomal Loop , 2008, Molecular and Cellular Biology.

[11]  N. Galjart,et al.  CTCF regulates cell cycle progression of αβ T cells in the thymus , 2008, The EMBO journal.

[12]  Samantha A. Morris,et al.  CellNet: Network Biology Applied to Stem Cell Engineering , 2014, Cell.

[13]  A. Consiglio,et al.  Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes , 2008, Nature Biotechnology.

[14]  Sumiko Watanabe,et al.  Molecular mechanisms of H3K27me3 and H3K4me3 in retinal development , 2019, Neuroscience Research.

[15]  Fu-Jung Lin,et al.  Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity , 2005, Nature.

[16]  B. Stillman.  Histone Modifications: Insights into Their Influence on Gene Expression , 2018, Cell.

[17]  N. Galjart,et al.  Dual Effect of CTCF Loss on Neuroprogenitor Differentiation and Survival , 2014, The Journal of Neuroscience.

[18]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[19]  Jiao Liu,et al.  Dynamic patterns of H3K4me3, H3K27me3, and Nanog during rabbit embryo development. , 2019, American journal of translational research.

[20]  Fuhui Long,et al.  Feature selection based on mutual information criteria of max-dependency, max-relevance, and min-redundancy , 2003, IEEE Transactions on Pattern Analysis and Machine Intelligence.

[21]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[22]  Michael Q. Zhang,et al.  CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function , 2015, Cell.

[23]  Keji Zhao,et al.  CTCF-Mediated Enhancer-Promoter Interaction Is a Critical Regulator of Cell-to-Cell Variation of Gene Expression. , 2017, Molecular cell.

[24]  Marcos J. Araúzo-Bravo,et al.  Oct4-Induced Pluripotency in Adult Neural Stem Cells , 2009, Cell.

[25]  Wai Lim Ku,et al.  Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin , 2016, Nature Genetics.

[26]  M. Crossley,et al.  The CtBP family: enigmatic and enzymatic transcriptional co‐repressors , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[27]  G. Church,et al.  Reprogramming of T cells from human peripheral blood. , 2010, Cell stem cell.

[28]  N. Galjart,et al.  Functional analysis of CTCF during mammalian limb development. , 2010, Developmental cell.

[29]  Peter H. L. Krijger,et al.  The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension , 2017, Cell.

[30]  Yuka Kanno,et al.  Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. , 2009, Immunity.

[31]  B. Ren,et al.  Metabolic regulation of gene expression by histone lactylation , 2019, Nature.

[32]  Jesse R. Dixon,et al.  Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells , 2013, Proceedings of the National Academy of Sciences.

[33]  R. Young,et al.  Super-Enhancers in the Control of Cell Identity and Disease , 2013, Cell.

[34]  Wenqiang Shi,et al.  Gene expression models based on transcription factor binding events confer insight into functional cis-regulatory variants , 2018, Bioinform..

[35]  N. D. Clarke,et al.  Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells , 2008, Cell.

[36]  Ting Wang,et al.  Track data hubs enable visualization of user-defined genome-wide annotations on the UCSC Genome Browser , 2013, Bioinform..

[37]  Mariano J. Alvarez,et al.  Genome-wide Identification of Post-translational Modulators of Transcription Factor Activity in Human B-Cells , 2009, Nature Biotechnology.

[38]  Hongxia Miao,et al.  Mutual information rate of nonstationary statistical signals , 2020, Signal Process..

[40]  Julia A. Lasserre,et al.  Histone modification levels are predictive for gene expression , 2010, Proceedings of the National Academy of Sciences.

[41]  L. Mirny,et al.  Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization , 2017, Cell.

[42]  David A. Orlando,et al.  Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes , 2013, Cell.

[43]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[44]  W. Herr,et al.  Leukemia Proto-Oncoprotein MLL Forms a SET1-Like Histone Methyltransferase Complex with Menin To Regulate Hox Gene Expression , 2004, Molecular and Cellular Biology.

[45]  Yong Zhang,et al.  Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos , 2016, Nature.

[46]  A. Bulinski,et al.  Statistical Estimation of Mutual Information for Mixed Model , 2020 .

[47]  A. West,et al.  The Protein CTCF Is Required for the Enhancer Blocking Activity of Vertebrate Insulators , 1999, Cell.

[48]  Danny Reinberg,et al.  Histone lysine methylation: a signature for chromatin function. , 2003, Trends in genetics : TIG.

[49]  Benjamin A. Garcia,et al.  Asymmetrically Modified Nucleosomes , 2012, Cell.

[50]  L. Steinmetz,et al.  Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency , 2018, Cell systems.

[51]  A. L. V. D. Wollenberg.  Redundancy analysis an alternative for canonical correlation analysis , 1977 .

[52]  Xi Chen,et al.  Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes , 2015, Nature Genetics.