Large DNA Methylation Nadirs Anchor Chromatin Loops Maintaining Hematopoietic Stem Cell Identity

Xiaotian Zhang; Mira Jeong; Xingfan Huang; Xue Qing Wang; Xinyu Wang; Wanding Zhou; Muhammad S Shamim; Haley Gore; Pamela Himadewi; Yushuai Liu; Ivan D Bochkov; Jaime Reyes; Madison Doty; Yung-Hsin Huang; Haiyoung Jung; Emily Heikamp; Aviva Presser Aiden; Wei Li; Jianzhong Su; Erez Lieberman Aiden; Margaret A Goodell

doi:10.1016/j.molcel.2020.04.018

Large DNA Methylation Nadirs Anchor Chromatin Loops Maintaining Hematopoietic Stem Cell Identity

Mol Cell. 2020 May 7;78(3):506-521.e6. doi: 10.1016/j.molcel.2020.04.018.

Authors

Xiaotian Zhang¹, Mira Jeong², Xingfan Huang³, Xue Qing Wang⁴, Xinyu Wang⁵, Wanding Zhou⁴, Muhammad S Shamim⁶, Haley Gore⁴, Pamela Himadewi⁴, Yushuai Liu⁴, Ivan D Bochkov⁷, Jaime Reyes⁸, Madison Doty⁹, Yung-Hsin Huang¹⁰, Haiyoung Jung¹¹, Emily Heikamp¹², Aviva Presser Aiden¹³, Wei Li¹⁴, Jianzhong Su⁵, Erez Lieberman Aiden¹⁵, Margaret A Goodell¹⁶

Affiliations

¹ Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA. Electronic address: zxtzhangqian@gmail.com.
² Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
³ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX, USA; Center for Theoretical Biological Physics & Department of Computer Science, Rice University, Houston, TX, USA.
⁴ Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
⁵ Institute of Biomedical Big Data, Wenzhou Medical University, Wenzhou, China.
⁶ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX, USA; Medical Student Training Program, Baylor College of Medicine, Houston, TX, USA; Center for Theoretical Biological Physics & Department of Computer Science, Rice University, Houston, TX, USA.
⁷ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁸ Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁹ Molecular Genetic Technology Program, School of Health Professions, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA; Developmental Biology Program, Baylor College of Medicine, Houston, TX, USA.
¹¹ Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA; Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Korea, USA.
¹² Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
¹³ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX, USA; Developmental Biology Program, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
¹⁴ Department of Bioinformatics, Biological Chemistry, University of California, Irvine CA, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
¹⁵ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX, USA; Center for Theoretical Biological Physics & Department of Computer Science, Rice University, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Shanghai Institute for Advanced Immunochemical Studies, Shanghai Tech University, Shanghai, China. Electronic address: erez@erez.com.
¹⁶ Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address: goodell@bcm.edu.

Abstract

Higher-order chromatin structure and DNA methylation are implicated in multiple developmental processes, but their relationship to cell state is unknown. Here, we find that large (>7.3 kb) DNA methylation nadirs (termed "grand canyons") can form long loops connecting anchor loci that may be dozens of megabases (Mb) apart, as well as inter-chromosomal links. The interacting loci cover a total of ∼3.5 Mb of the human genome. The strongest interactions are associated with repressive marks made by the Polycomb complex and are diminished upon EZH2 inhibitor treatment. The data are suggestive of the formation of these loops by interactions between repressive elements in the loci, forming a genomic subcompartment, rather than by cohesion/CTCF-mediated extrusion. Interestingly, unlike previously characterized subcompartments, these interactions are present only in particular cell types, such as stem and progenitor cells. Our work reveals that H3K27me3-marked large DNA methylation grand canyons represent a set of very-long-range loops associated with cellular identity.

Keywords: 3D genomics; CpG; DNA methylation; DNA methylation canyon; Polycomb; chromosomal looping; hematopoietic; self-renewal; stem cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

CCCTC-Binding Factor / genetics
CCCTC-Binding Factor / metabolism
Cell Differentiation
Chromatin / chemistry*
Chromatin / genetics*
Chromatin / metabolism
DNA Methylation*
Enhancer of Zeste Homolog 2 Protein / genetics
Enhancer of Zeste Homolog 2 Protein / metabolism
Epigenesis, Genetic
Gene Expression Regulation
Hematopoietic Stem Cells / cytology*
Hematopoietic Stem Cells / physiology*
Histones / genetics
Histones / metabolism
Homeodomain Proteins / genetics
Humans
In Situ Hybridization, Fluorescence
Lysine / genetics
Lysine / metabolism
Nuclear Proteins / genetics
SOXB1 Transcription Factors / genetics
Short Stature Homeobox Protein / genetics
Transcription Factors / genetics

Substances

CCCTC-Binding Factor
CTCF protein, human
Chromatin
Histones
Homeodomain Proteins
Nuclear Proteins
SHOX protein, human
SOX2 protein, human
SOXB1 Transcription Factors
Short Stature Homeobox Protein
Transcription Factors
ZIC2 protein, human
HoxA protein
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding