Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation

Robin D. Lee; Todd P. Knutson; Sarah A. Munro; Jeffrey T. Miller; Lynn M. Heltemes-Harris; Charles G. Mullighan; Kristen Jepsen; Michael A. Farrar

doi:10.1038/s41590-022-01343-7

Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation

Robin D. Lee, Todd P. Knutson, Sarah A. Munro, Jeffrey T. Miller, Lynn M. Heltemes-Harris, Charles G. Mullighan, Kristen Jepsen, Michael A. Farrar

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

Abstract

The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein, we demonstrate that Ncor1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR signaling and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, whereas human leukemias with less NCOR1 correlated with worse survival. NCOR1/2 mutations in human leukemia correlated with increased RAG expression and number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.

Original language	English (US)
Pages (from-to)	1763-1776
Number of pages	14
Journal	Nature immunology
Volume	23
Issue number	12
DOIs	https://doi.org/10.1038/s41590-022-01343-7
State	Published - Dec 2022

Bibliographical note

Funding Information:
C.G.M. provides consultation and advise for Illumina (compensated), Faze Medicines (compensated) and Beam Therapeutics (compensated) and receives research funding from Pfizer and Abbvie. The remaining authors declare no competing interests.

Funding Information:
We thank G. Hubbard, A. Rost and N. Keller for technical assistance and mouse husbandry; E. Stanley, J. Daniels and K. Beckman and the University of Minnesota Genomics Center for 10x Genomics single-cell capture and sequencing; J. Motl, R. Arora and P. Champoux for cell sorting and Flow Cytometry Core Facility maintenance at University of Minnesota (5P01AI035296); and S. Dehm and K. Schwertfeger (University of Minnesota) for comments on the manuscript. We thank E. Olson (UT-Southwestern), W. Ellmeier (Medical University of Vienna) and J. Auwerx (École Polytechnique Fédérale, Lausanne, Switzerland) for providing the Ncor1 mice. The Minnesota Supercomputing Institute at the University of Minnesota provided bioinformatic support and resources that contributed to the research results reported within this paper. We are thankful for support from the German Gene Trap Consortium, which assisted in the generation of the Ncor2 mice. This work was supported by an individual predoctoral F30 fellowship from the National Institutes of Health (NIH) (F30CA232399) and a T32 training grant (T32 GM008244) to R.D.L.; St Jude Children’s Research Hospital Cancer Center Core Grant CA021765 and NIH grant R35CA197695 to C.G.M.; and NIH grants R01AI124512, R01AI147540 and R01CA232317 to M.A.F. M.A.F. was supported by the Virginia and David Utz endowed chair in fundamental immunobiology. FL/FL FL/FL

Funding Information:
We thank G. Hubbard, A. Rost and N. Keller for technical assistance and mouse husbandry; E. Stanley, J. Daniels and K. Beckman and the University of Minnesota Genomics Center for 10x Genomics single-cell capture and sequencing; J. Motl, R. Arora and P. Champoux for cell sorting and Flow Cytometry Core Facility maintenance at University of Minnesota (5P01AI035296); and S. Dehm and K. Schwertfeger (University of Minnesota) for comments on the manuscript. We thank E. Olson (UT-Southwestern), W. Ellmeier (Medical University of Vienna) and J. Auwerx (École Polytechnique Fédérale, Lausanne, Switzerland) for providing the Ncor1FL/FLmice. The Minnesota Supercomputing Institute at the University of Minnesota provided bioinformatic support and resources that contributed to the research results reported within this paper. We are thankful for support from the German Gene Trap Consortium, which assisted in the generation of the Ncor2FL/FLmice. This work was supported by an individual predoctoral F30 fellowship from the National Institutes of Health (NIH) (F30CA232399) and a T32 training grant (T32 GM008244) to R.D.L.; St Jude Children’s Research Hospital Cancer Center Core Grant CA021765 and NIH grant R35CA197695 to C.G.M.; and NIH grants R01AI124512, R01AI147540 and R01CA232317 to M.A.F. M.A.F. was supported by the Virginia and David Utz endowed chair in fundamental immunobiology.

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© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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@article{8a88cdbbdb09418ea0391fe44b3b9b94,

title = "Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation",

abstract = "The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein, we demonstrate that Ncor1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR signaling and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, whereas human leukemias with less NCOR1 correlated with worse survival. NCOR1/2 mutations in human leukemia correlated with increased RAG expression and number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.",

author = "Lee, {Robin D.} and Knutson, {Todd P.} and Munro, {Sarah A.} and Miller, {Jeffrey T.} and Heltemes-Harris, {Lynn M.} and Mullighan, {Charles G.} and Kristen Jepsen and Farrar, {Michael A.}",

note = "Funding Information: C.G.M. provides consultation and advise for Illumina (compensated), Faze Medicines (compensated) and Beam Therapeutics (compensated) and receives research funding from Pfizer and Abbvie. The remaining authors declare no competing interests. Funding Information: We thank G. Hubbard, A. Rost and N. Keller for technical assistance and mouse husbandry; E. Stanley, J. Daniels and K. Beckman and the University of Minnesota Genomics Center for 10x Genomics single-cell capture and sequencing; J. Motl, R. Arora and P. Champoux for cell sorting and Flow Cytometry Core Facility maintenance at University of Minnesota (5P01AI035296); and S. Dehm and K. Schwertfeger (University of Minnesota) for comments on the manuscript. We thank E. Olson (UT-Southwestern), W. Ellmeier (Medical University of Vienna) and J. Auwerx ({\'E}cole Polytechnique F{\'e}d{\'e}rale, Lausanne, Switzerland) for providing the Ncor1 mice. The Minnesota Supercomputing Institute at the University of Minnesota provided bioinformatic support and resources that contributed to the research results reported within this paper. We are thankful for support from the German Gene Trap Consortium, which assisted in the generation of the Ncor2 mice. This work was supported by an individual predoctoral F30 fellowship from the National Institutes of Health (NIH) (F30CA232399) and a T32 training grant (T32 GM008244) to R.D.L.; St Jude Children{\textquoteright}s Research Hospital Cancer Center Core Grant CA021765 and NIH grant R35CA197695 to C.G.M.; and NIH grants R01AI124512, R01AI147540 and R01CA232317 to M.A.F. M.A.F. was supported by the Virginia and David Utz endowed chair in fundamental immunobiology. FL/FL FL/FL Funding Information: We thank G. Hubbard, A. Rost and N. Keller for technical assistance and mouse husbandry; E. Stanley, J. Daniels and K. Beckman and the University of Minnesota Genomics Center for 10x Genomics single-cell capture and sequencing; J. Motl, R. Arora and P. Champoux for cell sorting and Flow Cytometry Core Facility maintenance at University of Minnesota (5P01AI035296); and S. Dehm and K. Schwertfeger (University of Minnesota) for comments on the manuscript. We thank E. Olson (UT-Southwestern), W. Ellmeier (Medical University of Vienna) and J. Auwerx ({\'E}cole Polytechnique F{\'e}d{\'e}rale, Lausanne, Switzerland) for providing the Ncor1FL/FLmice. The Minnesota Supercomputing Institute at the University of Minnesota provided bioinformatic support and resources that contributed to the research results reported within this paper. We are thankful for support from the German Gene Trap Consortium, which assisted in the generation of the Ncor2FL/FLmice. This work was supported by an individual predoctoral F30 fellowship from the National Institutes of Health (NIH) (F30CA232399) and a T32 training grant (T32 GM008244) to R.D.L.; St Jude Children{\textquoteright}s Research Hospital Cancer Center Core Grant CA021765 and NIH grant R35CA197695 to C.G.M.; and NIH grants R01AI124512, R01AI147540 and R01CA232317 to M.A.F. M.A.F. was supported by the Virginia and David Utz endowed chair in fundamental immunobiology. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = dec,

doi = "10.1038/s41590-022-01343-7",

language = "English (US)",

volume = "23",

pages = "1763--1776",

journal = "Nature Immunology",

issn = "1529-2908",

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T1 - Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation

AU - Lee, Robin D.

AU - Knutson, Todd P.

AU - Munro, Sarah A.

AU - Miller, Jeffrey T.

AU - Heltemes-Harris, Lynn M.

AU - Mullighan, Charles G.

AU - Jepsen, Kristen

AU - Farrar, Michael A.

N1 - Funding Information: C.G.M. provides consultation and advise for Illumina (compensated), Faze Medicines (compensated) and Beam Therapeutics (compensated) and receives research funding from Pfizer and Abbvie. The remaining authors declare no competing interests. Funding Information: We thank G. Hubbard, A. Rost and N. Keller for technical assistance and mouse husbandry; E. Stanley, J. Daniels and K. Beckman and the University of Minnesota Genomics Center for 10x Genomics single-cell capture and sequencing; J. Motl, R. Arora and P. Champoux for cell sorting and Flow Cytometry Core Facility maintenance at University of Minnesota (5P01AI035296); and S. Dehm and K. Schwertfeger (University of Minnesota) for comments on the manuscript. We thank E. Olson (UT-Southwestern), W. Ellmeier (Medical University of Vienna) and J. Auwerx (École Polytechnique Fédérale, Lausanne, Switzerland) for providing the Ncor1 mice. The Minnesota Supercomputing Institute at the University of Minnesota provided bioinformatic support and resources that contributed to the research results reported within this paper. We are thankful for support from the German Gene Trap Consortium, which assisted in the generation of the Ncor2 mice. This work was supported by an individual predoctoral F30 fellowship from the National Institutes of Health (NIH) (F30CA232399) and a T32 training grant (T32 GM008244) to R.D.L.; St Jude Children’s Research Hospital Cancer Center Core Grant CA021765 and NIH grant R35CA197695 to C.G.M.; and NIH grants R01AI124512, R01AI147540 and R01CA232317 to M.A.F. M.A.F. was supported by the Virginia and David Utz endowed chair in fundamental immunobiology. FL/FL FL/FL Funding Information: We thank G. Hubbard, A. Rost and N. Keller for technical assistance and mouse husbandry; E. Stanley, J. Daniels and K. Beckman and the University of Minnesota Genomics Center for 10x Genomics single-cell capture and sequencing; J. Motl, R. Arora and P. Champoux for cell sorting and Flow Cytometry Core Facility maintenance at University of Minnesota (5P01AI035296); and S. Dehm and K. Schwertfeger (University of Minnesota) for comments on the manuscript. We thank E. Olson (UT-Southwestern), W. Ellmeier (Medical University of Vienna) and J. Auwerx (École Polytechnique Fédérale, Lausanne, Switzerland) for providing the Ncor1FL/FLmice. The Minnesota Supercomputing Institute at the University of Minnesota provided bioinformatic support and resources that contributed to the research results reported within this paper. We are thankful for support from the German Gene Trap Consortium, which assisted in the generation of the Ncor2FL/FLmice. This work was supported by an individual predoctoral F30 fellowship from the National Institutes of Health (NIH) (F30CA232399) and a T32 training grant (T32 GM008244) to R.D.L.; St Jude Children’s Research Hospital Cancer Center Core Grant CA021765 and NIH grant R35CA197695 to C.G.M.; and NIH grants R01AI124512, R01AI147540 and R01CA232317 to M.A.F. M.A.F. was supported by the Virginia and David Utz endowed chair in fundamental immunobiology. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022/12

Y1 - 2022/12

N2 - The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein, we demonstrate that Ncor1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR signaling and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, whereas human leukemias with less NCOR1 correlated with worse survival. NCOR1/2 mutations in human leukemia correlated with increased RAG expression and number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.

AB - The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein, we demonstrate that Ncor1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR signaling and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, whereas human leukemias with less NCOR1 correlated with worse survival. NCOR1/2 mutations in human leukemia correlated with increased RAG expression and number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.

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Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation

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