Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation

Aaron D Viny; Robert L Bowman; Yu Liu; Vincent-Philippe Lavallée; Shira E Eisman; Wenbin Xiao; Benjamin H Durham; Anastasia Navitski; Jane Park; Stephanie Braunstein; Besmira Alija; Abdul Karzai; Isabelle S Csete; Matthew Witkin; Elham Azizi; Timour Baslan; Christopher J Ott; Dana Pe'er; Job Dekker; Richard Koche; Ross L Levine

doi:10.1016/j.stem.2019.08.003

Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation

Aaron D Viny, Robert L Bowman, Yu Liu, Vincent-Philippe Lavallée, Shira E Eisman, Wenbin Xiao, Benjamin H Durham, Anastasia Navitski, Jane Park, Stephanie Braunstein, Besmira Alija, Abdul Karzai, Isabelle S Csete, Matthew Witkin, Elham Azizi, Timour Baslan, Christopher J Ott, Dana Pe'er, Job Dekker, Richard KocheRoss L Levine

Research output: Contribution to journal › Article › peer-review

108 Scopus citations

Abstract

Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.

Original language	English
Pages (from-to)	682-696.e8
Journal	Cell stem cell
Volume	25
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2019.08.003
State	Published - Nov 7 2019

Keywords

Animals
B-Lymphocytes/metabolism
Cell Cycle Proteins/genetics
Cell Lineage/genetics
Cell Self Renewal/genetics
Chromatin/metabolism
Chromatin Immunoprecipitation
Gene Expression Regulation/genetics
Gene Knockout Techniques
Hematopoiesis/genetics
Hematopoietic Stem Cells/cytology
Humans
Membrane Proteins/genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myelodysplastic Syndromes/genetics
Nuclear Proteins/genetics
PAX5 Transcription Factor/genetics
RNA-Seq
Synthetic Lethal Mutations/genetics
Trans-Activators/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stem.2019.08.003

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Viny, A. D., Bowman, R. L., Liu, Y., Lavallée, V.-P., Eisman, S. E., Xiao, W., Durham, B. H., Navitski, A., Park, J., Braunstein, S., Alija, B., Karzai, A., Csete, I. S., Witkin, M., Azizi, E., Baslan, T., Ott, C. J., Pe'er, D., Dekker, J., ... Levine, R. L. (2019). Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation. Cell stem cell, 25(5), 682-696.e8. https://doi.org/10.1016/j.stem.2019.08.003

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title = "Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation",

abstract = "Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.",

keywords = "Animals, B-Lymphocytes/metabolism, Cell Cycle Proteins/genetics, Cell Lineage/genetics, Cell Self Renewal/genetics, Chromatin/metabolism, Chromatin Immunoprecipitation, Gene Expression Regulation/genetics, Gene Knockout Techniques, Hematopoiesis/genetics, Hematopoietic Stem Cells/cytology, Humans, Membrane Proteins/genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myelodysplastic Syndromes/genetics, Nuclear Proteins/genetics, PAX5 Transcription Factor/genetics, RNA-Seq, Synthetic Lethal Mutations/genetics, Trans-Activators/genetics",

author = "Viny, {Aaron D} and Bowman, {Robert L} and Yu Liu and Vincent-Philippe Lavall{\'e}e and Eisman, {Shira E} and Wenbin Xiao and Durham, {Benjamin H} and Anastasia Navitski and Jane Park and Stephanie Braunstein and Besmira Alija and Abdul Karzai and Csete, {Isabelle S} and Matthew Witkin and Elham Azizi and Timour Baslan and Ott, {Christopher J} and Dana Pe'er and Job Dekker and Richard Koche and Levine, {Ross L}",

year = "2019",

month = nov,

day = "7",

doi = "10.1016/j.stem.2019.08.003",

language = "English",

volume = "25",

pages = "682--696.e8",

journal = "Cell stem cell",

issn = "1875-9777",

publisher = "Cell Press",

number = "5",

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Viny, AD, Bowman, RL, Liu, Y, Lavallée, V-P, Eisman, SE, Xiao, W, Durham, BH, Navitski, A, Park, J, Braunstein, S, Alija, B, Karzai, A, Csete, IS, Witkin, M, Azizi, E, Baslan, T, Ott, CJ, Pe'er, D, Dekker, J, Koche, R & Levine, RL 2019, 'Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation', Cell stem cell, vol. 25, no. 5, pp. 682-696.e8. https://doi.org/10.1016/j.stem.2019.08.003

TY - JOUR

T1 - Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation

AU - Viny, Aaron D

AU - Bowman, Robert L

AU - Liu, Yu

AU - Lavallée, Vincent-Philippe

AU - Eisman, Shira E

AU - Xiao, Wenbin

AU - Durham, Benjamin H

AU - Navitski, Anastasia

AU - Park, Jane

AU - Braunstein, Stephanie

AU - Alija, Besmira

AU - Karzai, Abdul

AU - Csete, Isabelle S

AU - Witkin, Matthew

AU - Azizi, Elham

AU - Baslan, Timour

AU - Ott, Christopher J

AU - Pe'er, Dana

AU - Dekker, Job

AU - Koche, Richard

AU - Levine, Ross L

PY - 2019/11/7

Y1 - 2019/11/7

N2 - Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.

AB - Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.

KW - Animals

KW - B-Lymphocytes/metabolism

KW - Cell Cycle Proteins/genetics

KW - Cell Lineage/genetics

KW - Cell Self Renewal/genetics

KW - Chromatin/metabolism

KW - Chromatin Immunoprecipitation

KW - Gene Expression Regulation/genetics

KW - Gene Knockout Techniques

KW - Hematopoiesis/genetics

KW - Hematopoietic Stem Cells/cytology

KW - Humans

KW - Membrane Proteins/genetics

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Myelodysplastic Syndromes/genetics

KW - Nuclear Proteins/genetics

KW - PAX5 Transcription Factor/genetics

KW - RNA-Seq

KW - Synthetic Lethal Mutations/genetics

KW - Trans-Activators/genetics

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U2 - 10.1016/j.stem.2019.08.003

DO - 10.1016/j.stem.2019.08.003

M3 - Article

C2 - 31495782

SN - 1875-9777

VL - 25

SP - 682-696.e8

JO - Cell stem cell

JF - Cell stem cell

IS - 5

ER -

Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation

Abstract

Keywords

UN SDGs

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