NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain

Sanxiong Liu; Kimberly A. Aldinger; Chi Vicky Cheng; Takae Kiyama; Mitali Dave; Hanna K. McNamara; Wukui Zhao; James M. Stafford; Nicolas Descostes; Pedro Lee; Stefano G. Caraffi; Ivan Ivanovski; Edoardo Errichiello; Christiane Zweier; Orsetta Zuffardi; Michael Schneider; Antigone S. Papavasiliou; M. Scott Perry; Jennifer Humberson; Megan T. Cho; Astrid Weber; Andrew Swale; Tudor C. Badea; Chai An Mao; Livia Garavelli; William B. Dobyns; Danny Reinberg

doi:10.1016/j.molcel.2021.09.020

NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain

Sanxiong Liu, Kimberly A. Aldinger, Chi Vicky Cheng, Takae Kiyama, Mitali Dave, Hanna K. McNamara, Wukui Zhao, James M. Stafford, Nicolas Descostes, Pedro Lee, Stefano G. Caraffi, Ivan Ivanovski, Edoardo Errichiello, Christiane Zweier, Orsetta Zuffardi, Michael Schneider, Antigone S. Papavasiliou, M. Scott Perry, Jennifer Humberson, Megan T. ChoAstrid Weber, Andrew Swale, Tudor C. Badea, Chai An Mao, Livia Garavelli, William B. Dobyns, Danny Reinberg

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

18 Scopus citations

Abstract

The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.

Original language	English (US)
Pages (from-to)	4663-4676.e8
Journal	Molecular Cell
Volume	81
Issue number	22
DOIs	https://doi.org/10.1016/j.molcel.2021.09.020
State	Published - Nov 18 2021
Externally published	Yes

Bibliographical note

Funding Information:
We thank Drs. Lynne Vales, Esteban Mazzoni, and Anne Schaefer for critical reading of the manuscript as well as past and current Reinberg laboratory members for critical comments and discussions. We also thank the New York University Langone Medical Center (NYULMC) Genome Technology Center for help with sequencing, the NYULMC Cytometry and Cell Sorting Core for help with FACS, and the NYULMC Animal Facility for help with mouse housing. This study utilized computing resources at the High-Performance Computing Facility of the Center for Health Informatics and Bioinformatics at the NYULMC. C.-A.M. and T.K. are supported by grants from the National Institutes of Health - National Eye Institute ( EY024376 and P30EY028102 ). The work in the Reinberg lab is supported by the NIH ( R01NS100897 and R01CA199652 to D.R.), the Simon Foundation ( 240344 to D.R.), and the Howard Hughes Medical Institute . J.M.S. was supported by a junior fellow award from the Simons Foundation and by an NIH grant ( K99AA024837 ).

Funding Information:
We thank Drs. Lynne Vales, Esteban Mazzoni, and Anne Schaefer for critical reading of the manuscript as well as past and current Reinberg laboratory members for critical comments and discussions. We also thank the New York University Langone Medical Center (NYULMC) Genome Technology Center for help with sequencing, the NYULMC Cytometry and Cell Sorting Core for help with FACS, and the NYULMC Animal Facility for help with mouse housing. This study utilized computing resources at the High-Performance Computing Facility of the Center for Health Informatics and Bioinformatics at the NYULMC. C.-A.M. and T.K. are supported by grants from the National Institutes of Health-National Eye Institute (EY024376 and P30EY028102). The work in the Reinberg lab is supported by the NIH (R01NS100897 and R01CA199652 to D.R.), the Simon Foundation (240344 to D.R.), and the Howard Hughes Medical Institute. J.M.S. was supported by a junior fellow award from the Simons Foundation and by an NIH grant (K99AA024837). S.L. and D.R. conceived the project, designed the experiments, and wrote the paper. S.L. performed the vast majority of the experiments and all bioinformatics analyses. K.A.A. C.V.C. M.D. and H.K.M. performed the clinical and genetic analyses under the supervision of W.B.D. W.Z. helped with the luciferase assay. J.M.S. N.D. and P.L. helped with the ChIP-seq and IP-MS in mouse brain. S.G.C. I.I. E.E. C.Z. O.Z. M.S. A.S.P. M.S.P. J.H. M.T.C. A.W. A.S. and L.G. collected the clinical data. T.K. performed the Nrf1 mouse studies under the supervision of T.C.B. and C.-A.M. D.R. supervised the study. D.R. is a cofounder of Constellation and Fulcrum Pharmaceuticals.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

AUTS2
NRF1
P300
RSTS
active transcription
brain development
ncPRC1.3
polycomb

UN SDGs

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

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Liu, S., Aldinger, K. A., Cheng, C. V., Kiyama, T., Dave, M., McNamara, H. K., Zhao, W., Stafford, J. M., Descostes, N., Lee, P., Caraffi, S. G., Ivanovski, I., Errichiello, E., Zweier, C., Zuffardi, O., Schneider, M., Papavasiliou, A. S., Perry, M. S., Humberson, J., ... Reinberg, D. (2021). NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain. Molecular Cell, 81(22), 4663-4676.e8. https://doi.org/10.1016/j.molcel.2021.09.020

Liu, S, Aldinger, KA, Cheng, CV, Kiyama, T, Dave, M, McNamara, HK, Zhao, W, Stafford, JM, Descostes, N, Lee, P, Caraffi, SG, Ivanovski, I, Errichiello, E, Zweier, C, Zuffardi, O, Schneider, M, Papavasiliou, AS, Perry, MS, Humberson, J, Cho, MT, Weber, A, Swale, A, Badea, TC, Mao, CA, Garavelli, L, Dobyns, WB & Reinberg, D 2021, 'NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain', Molecular Cell, vol. 81, no. 22, pp. 4663-4676.e8. https://doi.org/10.1016/j.molcel.2021.09.020

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title = "NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain",

abstract = "The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.",

keywords = "AUTS2, NRF1, P300, RSTS, active transcription, brain development, ncPRC1.3, polycomb",

author = "Sanxiong Liu and Aldinger, {Kimberly A.} and Cheng, {Chi Vicky} and Takae Kiyama and Mitali Dave and McNamara, {Hanna K.} and Wukui Zhao and Stafford, {James M.} and Nicolas Descostes and Pedro Lee and Caraffi, {Stefano G.} and Ivan Ivanovski and Edoardo Errichiello and Christiane Zweier and Orsetta Zuffardi and Michael Schneider and Papavasiliou, {Antigone S.} and Perry, {M. Scott} and Jennifer Humberson and Cho, {Megan T.} and Astrid Weber and Andrew Swale and Badea, {Tudor C.} and Mao, {Chai An} and Livia Garavelli and Dobyns, {William B.} and Danny Reinberg",

note = "Funding Information: We thank Drs. Lynne Vales, Esteban Mazzoni, and Anne Schaefer for critical reading of the manuscript as well as past and current Reinberg laboratory members for critical comments and discussions. We also thank the New York University Langone Medical Center (NYULMC) Genome Technology Center for help with sequencing, the NYULMC Cytometry and Cell Sorting Core for help with FACS, and the NYULMC Animal Facility for help with mouse housing. This study utilized computing resources at the High-Performance Computing Facility of the Center for Health Informatics and Bioinformatics at the NYULMC. C.-A.M. and T.K. are supported by grants from the National Institutes of Health - National Eye Institute ( EY024376 and P30EY028102 ). The work in the Reinberg lab is supported by the NIH ( R01NS100897 and R01CA199652 to D.R.), the Simon Foundation ( 240344 to D.R.), and the Howard Hughes Medical Institute . J.M.S. was supported by a junior fellow award from the Simons Foundation and by an NIH grant ( K99AA024837 ). Funding Information: We thank Drs. Lynne Vales, Esteban Mazzoni, and Anne Schaefer for critical reading of the manuscript as well as past and current Reinberg laboratory members for critical comments and discussions. We also thank the New York University Langone Medical Center (NYULMC) Genome Technology Center for help with sequencing, the NYULMC Cytometry and Cell Sorting Core for help with FACS, and the NYULMC Animal Facility for help with mouse housing. This study utilized computing resources at the High-Performance Computing Facility of the Center for Health Informatics and Bioinformatics at the NYULMC. C.-A.M. and T.K. are supported by grants from the National Institutes of Health-National Eye Institute (EY024376 and P30EY028102). The work in the Reinberg lab is supported by the NIH (R01NS100897 and R01CA199652 to D.R.), the Simon Foundation (240344 to D.R.), and the Howard Hughes Medical Institute. J.M.S. was supported by a junior fellow award from the Simons Foundation and by an NIH grant (K99AA024837). S.L. and D.R. conceived the project, designed the experiments, and wrote the paper. S.L. performed the vast majority of the experiments and all bioinformatics analyses. K.A.A. C.V.C. M.D. and H.K.M. performed the clinical and genetic analyses under the supervision of W.B.D. W.Z. helped with the luciferase assay. J.M.S. N.D. and P.L. helped with the ChIP-seq and IP-MS in mouse brain. S.G.C. I.I. E.E. C.Z. O.Z. M.S. A.S.P. M.S.P. J.H. M.T.C. A.W. A.S. and L.G. collected the clinical data. T.K. performed the Nrf1 mouse studies under the supervision of T.C.B. and C.-A.M. D.R. supervised the study. D.R. is a cofounder of Constellation and Fulcrum Pharmaceuticals. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = nov,

day = "18",

doi = "10.1016/j.molcel.2021.09.020",

language = "English (US)",

volume = "81",

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T1 - NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain

AU - Liu, Sanxiong

AU - Aldinger, Kimberly A.

AU - Cheng, Chi Vicky

AU - Kiyama, Takae

AU - Dave, Mitali

AU - McNamara, Hanna K.

AU - Zhao, Wukui

AU - Stafford, James M.

AU - Descostes, Nicolas

AU - Lee, Pedro

AU - Caraffi, Stefano G.

AU - Ivanovski, Ivan

AU - Errichiello, Edoardo

AU - Zweier, Christiane

AU - Zuffardi, Orsetta

AU - Schneider, Michael

AU - Papavasiliou, Antigone S.

AU - Perry, M. Scott

AU - Humberson, Jennifer

AU - Cho, Megan T.

AU - Weber, Astrid

AU - Swale, Andrew

AU - Badea, Tudor C.

AU - Mao, Chai An

AU - Garavelli, Livia

AU - Dobyns, William B.

AU - Reinberg, Danny

N1 - Funding Information: We thank Drs. Lynne Vales, Esteban Mazzoni, and Anne Schaefer for critical reading of the manuscript as well as past and current Reinberg laboratory members for critical comments and discussions. We also thank the New York University Langone Medical Center (NYULMC) Genome Technology Center for help with sequencing, the NYULMC Cytometry and Cell Sorting Core for help with FACS, and the NYULMC Animal Facility for help with mouse housing. This study utilized computing resources at the High-Performance Computing Facility of the Center for Health Informatics and Bioinformatics at the NYULMC. C.-A.M. and T.K. are supported by grants from the National Institutes of Health - National Eye Institute ( EY024376 and P30EY028102 ). The work in the Reinberg lab is supported by the NIH ( R01NS100897 and R01CA199652 to D.R.), the Simon Foundation ( 240344 to D.R.), and the Howard Hughes Medical Institute . J.M.S. was supported by a junior fellow award from the Simons Foundation and by an NIH grant ( K99AA024837 ). Funding Information: We thank Drs. Lynne Vales, Esteban Mazzoni, and Anne Schaefer for critical reading of the manuscript as well as past and current Reinberg laboratory members for critical comments and discussions. We also thank the New York University Langone Medical Center (NYULMC) Genome Technology Center for help with sequencing, the NYULMC Cytometry and Cell Sorting Core for help with FACS, and the NYULMC Animal Facility for help with mouse housing. This study utilized computing resources at the High-Performance Computing Facility of the Center for Health Informatics and Bioinformatics at the NYULMC. C.-A.M. and T.K. are supported by grants from the National Institutes of Health-National Eye Institute (EY024376 and P30EY028102). The work in the Reinberg lab is supported by the NIH (R01NS100897 and R01CA199652 to D.R.), the Simon Foundation (240344 to D.R.), and the Howard Hughes Medical Institute. J.M.S. was supported by a junior fellow award from the Simons Foundation and by an NIH grant (K99AA024837). S.L. and D.R. conceived the project, designed the experiments, and wrote the paper. S.L. performed the vast majority of the experiments and all bioinformatics analyses. K.A.A. C.V.C. M.D. and H.K.M. performed the clinical and genetic analyses under the supervision of W.B.D. W.Z. helped with the luciferase assay. J.M.S. N.D. and P.L. helped with the ChIP-seq and IP-MS in mouse brain. S.G.C. I.I. E.E. C.Z. O.Z. M.S. A.S.P. M.S.P. J.H. M.T.C. A.W. A.S. and L.G. collected the clinical data. T.K. performed the Nrf1 mouse studies under the supervision of T.C.B. and C.-A.M. D.R. supervised the study. D.R. is a cofounder of Constellation and Fulcrum Pharmaceuticals. Publisher Copyright: © 2021 Elsevier Inc.

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Y1 - 2021/11/18

N2 - The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.

AB - The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.

KW - AUTS2

KW - NRF1

KW - P300

KW - RSTS

KW - active transcription

KW - brain development

KW - ncPRC1.3

KW - polycomb

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ER -

NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain

Abstract

Bibliographical note

Keywords

UN SDGs

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