Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration

Sima Khazaei; Carol C.L. Chen; Augusto Faria Andrade; Nisha Kabir; Pariya Azarafshar; Shahir M. Morcos; Josiane Alves França; Mariana Lopes; Peder J. Lund; Geoffroy Danieau; Samantha Worme; Lata Adnani; Nadine Nzirorera; Xiao Chen; Gayathri Yogarajah; Caterina Russo; Michele Zeinieh; Cassandra J. Wong; Laura Bryant; Steven Hébert; Bethany Tong; Tianna S. Sihota; Damien Faury; Evan Puligandla; Wajih Jawhar; Veronica Sandy; Mitra Cowan; Emily M. Nakada; Loydie A. Jerome-Majewska; Benjamin Ellezam; Carolina Cavalieri Gomes; Jonas Denecke; Davor Lessel; Marie T. McDonald; Carolyn E. Pizoli; Kathryn Taylor; Benjamin T. Cocanougher; Elizabeth J. Bhoj; Anne Claude Gingras; Benjamin A. Garcia; Chao Lu; Eric I. Campos; Claudia L. Kleinman; Livia Garzia; Nada Jabado

doi:10.1016/j.cell.2023.02.023

Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration

Sima Khazaei, Carol C.L. Chen, Augusto Faria Andrade, Nisha Kabir, Pariya Azarafshar, Shahir M. Morcos, Josiane Alves França, Mariana Lopes, Peder J. Lund, Geoffroy Danieau, Samantha Worme, Lata Adnani, Nadine Nzirorera, Xiao Chen, Gayathri Yogarajah, Caterina Russo, Michele Zeinieh, Cassandra J. Wong, Laura Bryant, Steven HébertBethany Tong, Tianna S. Sihota, Damien Faury, Evan Puligandla, Wajih Jawhar, Veronica Sandy, Mitra Cowan, Emily M. Nakada, Loydie A. Jerome-Majewska, Benjamin Ellezam, Carolina Cavalieri Gomes, Jonas Denecke, Davor Lessel, Marie T. McDonald, Carolyn E. Pizoli, Kathryn Taylor, Benjamin T. Cocanougher, Elizabeth J. Bhoj, Anne Claude Gingras, Benjamin A. Garcia, Chao Lu, Eric I. Campos, Claudia L. Kleinman, Livia Garzia, Nada Jabado

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

3 Scopus citations

Abstract

Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated H3.3G34R/V/W knock-in mice and identified strikingly distinct developmental defects for each mutation. H3.3G34R-mutants exhibited progressive microcephaly and neurodegeneration, with abnormal accumulation of disease-associated microglia and concurrent neuronal depletion. G34R severely decreased H3K36me2 on the mutant H3.3 tail, impairing recruitment of DNA methyltransferase DNMT3A and its redistribution on chromatin. These changes were concurrent with sustained expression of complement and other innate immune genes possibly through loss of non-CG (CH) methylation and silencing of neuronal gene promoters through aberrant CG methylation. Complement expression in G34R brains may lead to neuroinflammation possibly accounting for progressive neurodegeneration. Our study reveals that H3.3G34-substitutions have differential impact on the epigenome, which underlie the diverse phenotypes observed, and uncovers potential roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating synaptic pruning and neuroinflammation in post-natal brains.

Original language	English
Pages (from-to)	1162-1178.e20
Journal	Cell
Volume	186
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2023.02.023
State	Published - Mar 16 2023

Keywords

CH methylation
DNA methylation
DNMT3A
H3.3 G34R/V/W
H3K36me2
complement
neurodegeneration
neuroinflammation
oncohistones
synaptic pruning

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10.1016/j.cell.2023.02.023

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Khazaei, S., Chen, C. C. L., Andrade, A. F., Kabir, N., Azarafshar, P., Morcos, S. M., França, J. A., Lopes, M., Lund, P. J., Danieau, G., Worme, S., Adnani, L., Nzirorera, N., Chen, X., Yogarajah, G., Russo, C., Zeinieh, M., Wong, C. J., Bryant, L., ... Jabado, N. (2023). Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration. Cell, 186(6), 1162-1178.e20. https://doi.org/10.1016/j.cell.2023.02.023

@article{8ac1093eb5534c0299b72ac13c7a24cf,

title = "Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration",

abstract = "Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated H3.3G34R/V/W knock-in mice and identified strikingly distinct developmental defects for each mutation. H3.3G34R-mutants exhibited progressive microcephaly and neurodegeneration, with abnormal accumulation of disease-associated microglia and concurrent neuronal depletion. G34R severely decreased H3K36me2 on the mutant H3.3 tail, impairing recruitment of DNA methyltransferase DNMT3A and its redistribution on chromatin. These changes were concurrent with sustained expression of complement and other innate immune genes possibly through loss of non-CG (CH) methylation and silencing of neuronal gene promoters through aberrant CG methylation. Complement expression in G34R brains may lead to neuroinflammation possibly accounting for progressive neurodegeneration. Our study reveals that H3.3G34-substitutions have differential impact on the epigenome, which underlie the diverse phenotypes observed, and uncovers potential roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating synaptic pruning and neuroinflammation in post-natal brains.",

keywords = "CH methylation, DNA methylation, DNMT3A, H3.3 G34R/V/W, H3K36me2, complement, neurodegeneration, neuroinflammation, oncohistones, synaptic pruning",

author = "Sima Khazaei and Chen, {Carol C.L.} and Andrade, {Augusto Faria} and Nisha Kabir and Pariya Azarafshar and Morcos, {Shahir M.} and Fran{\c c}a, {Josiane Alves} and Mariana Lopes and Lund, {Peder J.} and Geoffroy Danieau and Samantha Worme and Lata Adnani and Nadine Nzirorera and Xiao Chen and Gayathri Yogarajah and Caterina Russo and Michele Zeinieh and Wong, {Cassandra J.} and Laura Bryant and Steven H{\'e}bert and Bethany Tong and Sihota, {Tianna S.} and Damien Faury and Evan Puligandla and Wajih Jawhar and Veronica Sandy and Mitra Cowan and Nakada, {Emily M.} and Jerome-Majewska, {Loydie A.} and Benjamin Ellezam and Gomes, {Carolina Cavalieri} and Jonas Denecke and Davor Lessel and McDonald, {Marie T.} and Pizoli, {Carolyn E.} and Kathryn Taylor and Cocanougher, {Benjamin T.} and Bhoj, {Elizabeth J.} and Gingras, {Anne Claude} and Garcia, {Benjamin A.} and Chao Lu and Campos, {Eric I.} and Kleinman, {Claudia L.} and Livia Garzia and Nada Jabado",

note = "Funding Information: This work was supported by a Large-Scale-Applied-Research-Project from G{\'e}nome Quebec ( GQ ), Genome Canada , with the support of the Ontario Research Fund through funding provided by the Government of Ontario to N.J., C.L.K., and L.G. Additional support came from grant #25056 from the Cancer Research Society , GQ and Minist{\`e}re de l{\textquoteright}{\'E}conomie et de l{\textquoteright}Innovation du Qu{\'e}bec . Additional funding support was provided by Fondation Charles-Bruneau and National Institutes of Health (NIH) grant P01-CA196539 (to N.J.), R01- R01CA255369 (to L.G.), R01-CA266978 and R35-GM138181 (to C.L.); Canadian Institutes of Health Research (CIHR) grants MOP-286756 and FDN-154307 (to N.J.) and PJT-156086 (to C.L.K.); Canadian Cancer Society grant 705182 and 705799 (to L.G.), a Fonds de Recherche du Qu{\'e}bec – Sant{\'e} ( FRQS ) salary award (to C.L.K. and L.G.); NSERC RGPIN-2016-04911 (to C.L.K.); CFI Leaders Opportunity Fund 33902 (to C.L.K.); and Genome Canada Science Technology Innovation Center, McGill Genome Center, Compute Canada Resource Allocation Projects MJD-574-AC and WST-164-AB . Data analyses were enabled by computing and storage resources provided by Compute Canada and Calcul Qu{\'e}bec. Mass spectrometry data was generated at the Network Biology Collaborative Center (NBCC), a facility supported by Canada Foundation for Innovation funding (Grant CFI 33474 ), the Ontario Government , Genome Canada , and Ontario Genomics ( OGI-139 ). N.J. is a member of the Penny Cole Laboratory and holds a Canada Research Chair (CRC) Tier 1 in Pediatric Oncology from CIHR; A.-C.G. is a CRC for Functional Proteomics. C.C.L.C. is supported by a fellowship from RI-MUHC sponsored by Toronto Dominion Bank and Alex's Lemonade Stand Foundation . B.A.G. is funded by NIH grants CA196539 and AI118891 , and the St. Jude Chromatin Consortium . E.I.C. is supported by CIHR ( PJT-159683 ), the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN-2016-05559 ), the Cancer Research Society , and the Garron Family Cancer Centre . S.M.M. is supported by a University of Toronto Open Fellowship. J.A.F. and C.C.G. were financed by the National Council for Scientific and Technological Development (CNPq)/Brazil and Coordination for the Improvement of Higher Education Personnel (CAPES)/Brazil Scholarship PDSE 88881.187783/2018-01 . Funding is acknowledged from the Crohn's and Colitis Foundation ( RFA 598467 to P.J.L.) and the NIH ( T32CA009140 to P.J.L.). Some figures were created using BioRender.com . Funding Information: This work was supported by a Large-Scale-Applied-Research-Project from G{\'e}nome Quebec (GQ), Genome Canada, with the support of the Ontario Research Fund through funding provided by the Government of Ontario to N.J. C.L.K. and L.G. Additional support came from grant #25056 from the Cancer Research Society, GQ and Minist{\`e}re de l{\textquoteright}{\'E}conomie et de l'Innovation du Qu{\'e}bec. Additional funding support was provided by Fondation Charles-Bruneau and National Institutes of Health (NIH) grant P01-CA196539 (to N.J.), R01- R01CA255369 (to L.G.), R01-CA266978 and R35-GM138181 (to C.L.); Canadian Institutes of Health Research (CIHR) grants MOP-286756 and FDN-154307 (to N.J.) and PJT-156086 (to C.L.K.); Canadian Cancer Society grant 705182 and 705799 (to L.G.), a Fonds de Recherche du Qu{\'e}bec – Sant{\'e} (FRQS) salary award (to C.L.K. and L.G.); NSERC RGPIN-2016-04911 (to C.L.K.); CFI Leaders Opportunity Fund 33902 (to C.L.K.); and Genome Canada Science Technology Innovation Center, McGill Genome Center, Compute Canada Resource Allocation Projects MJD-574-AC and WST-164-AB. Data analyses were enabled by computing and storage resources provided by Compute Canada and Calcul Qu{\'e}bec. Mass spectrometry data was generated at the Network Biology Collaborative Center (NBCC), a facility supported by Canada Foundation for Innovation funding (Grant CFI 33474), the Ontario Government, Genome Canada, and Ontario Genomics (OGI-139). N.J. is a member of the Penny Cole Laboratory and holds a Canada Research Chair (CRC) Tier 1 in Pediatric Oncology from CIHR; A.-C.G. is a CRC for Functional Proteomics. C.C.L.C. is supported by a fellowship from RI-MUHC sponsored by Toronto Dominion Bank and Alex's Lemonade Stand Foundation. B.A.G. is funded by NIH grants CA196539 and AI118891, and the St. Jude Chromatin Consortium. E.I.C. is supported by CIHR (PJT-159683), the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN-2016-05559), the Cancer Research Society, and the Garron Family Cancer Centre. S.M.M. is supported by a University of Toronto Open Fellowship. J.A.F. and C.C.G. were financed by the National Council for Scientific and Technological Development (CNPq)/Brazil and Coordination for the Improvement of Higher Education Personnel (CAPES)/Brazil Scholarship PDSE 88881.187783/2018-01. Funding is acknowledged from the Crohn's and Colitis Foundation (RFA 598467 to P.J.L.) and the NIH (T32CA009140 to P.J.L.). Some figures were created using BioRender.com. Conceived and designed the analysis: S.K. C.C.L.C. A.F.A. C.L.K. L.G. N.J. Collected the data: S.K. C.C.L.C. P.A. A.F.A. S.M.M. J.A.F. M.L. P.J.L. G.Y. C.R. M.Z. C.J.W. L.B. B.T. T.S.S. V.S. M.C. J.D. D.L. M.T.M. C.E.P. K.T. B.T.C. E.J.B. Contributed data or analysis tools: C.C.L.C. N.K. L.A. X.C. S.H. B.E. L.A.J.-M. D.F. A.-C.G. B.A.G. C.L. E.I.C. C.L.K. L.G. N.J. Performed the analysis: S.K. C.C.L.C. A.F.A. N.K. M.L. P.J.L. L.A. X.C. C.J.W. E.I.C. L.G. Other contributions: E.M.N. (biobank manager), C.C.G. (supervision). Wrote the paper: S.K. C.C.L.C. A.F.A. C.L.K. L.G. N.J. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = mar,

day = "16",

doi = "10.1016/j.cell.2023.02.023",

language = "English",

volume = "186",

pages = "1162--1178.e20",

journal = "Cell",

issn = "0092-8674",

number = "6",

}

Khazaei, S, Chen, CCL, Andrade, AF, Kabir, N, Azarafshar, P, Morcos, SM, França, JA, Lopes, M, Lund, PJ, Danieau, G, Worme, S, Adnani, L, Nzirorera, N, Chen, X, Yogarajah, G, Russo, C, Zeinieh, M, Wong, CJ, Bryant, L, Hébert, S, Tong, B, Sihota, TS, Faury, D, Puligandla, E, Jawhar, W, Sandy, V, Cowan, M, Nakada, EM, Jerome-Majewska, LA, Ellezam, B, Gomes, CC, Denecke, J, Lessel, D, McDonald, MT, Pizoli, CE, Taylor, K, Cocanougher, BT, Bhoj, EJ, Gingras, AC, Garcia, BA, Lu, C, Campos, EI, Kleinman, CL, Garzia, L & Jabado, N 2023, 'Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration', Cell, vol. 186, no. 6, pp. 1162-1178.e20. https://doi.org/10.1016/j.cell.2023.02.023

TY - JOUR

T1 - Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration

AU - Khazaei, Sima

AU - Chen, Carol C.L.

AU - Andrade, Augusto Faria

AU - Kabir, Nisha

AU - Azarafshar, Pariya

AU - Morcos, Shahir M.

AU - França, Josiane Alves

AU - Lopes, Mariana

AU - Lund, Peder J.

AU - Danieau, Geoffroy

AU - Worme, Samantha

AU - Adnani, Lata

AU - Nzirorera, Nadine

AU - Chen, Xiao

AU - Yogarajah, Gayathri

AU - Russo, Caterina

AU - Zeinieh, Michele

AU - Wong, Cassandra J.

AU - Bryant, Laura

AU - Hébert, Steven

AU - Tong, Bethany

AU - Sihota, Tianna S.

AU - Faury, Damien

AU - Puligandla, Evan

AU - Jawhar, Wajih

AU - Sandy, Veronica

AU - Cowan, Mitra

AU - Nakada, Emily M.

AU - Jerome-Majewska, Loydie A.

AU - Ellezam, Benjamin

AU - Gomes, Carolina Cavalieri

AU - Denecke, Jonas

AU - Lessel, Davor

AU - McDonald, Marie T.

AU - Pizoli, Carolyn E.

AU - Taylor, Kathryn

AU - Cocanougher, Benjamin T.

AU - Bhoj, Elizabeth J.

AU - Gingras, Anne Claude

AU - Garcia, Benjamin A.

AU - Lu, Chao

AU - Campos, Eric I.

AU - Kleinman, Claudia L.

AU - Garzia, Livia

AU - Jabado, Nada

N1 - Funding Information: This work was supported by a Large-Scale-Applied-Research-Project from Génome Quebec ( GQ ), Genome Canada , with the support of the Ontario Research Fund through funding provided by the Government of Ontario to N.J., C.L.K., and L.G. Additional support came from grant #25056 from the Cancer Research Society , GQ and Ministère de l’Économie et de l’Innovation du Québec . Additional funding support was provided by Fondation Charles-Bruneau and National Institutes of Health (NIH) grant P01-CA196539 (to N.J.), R01- R01CA255369 (to L.G.), R01-CA266978 and R35-GM138181 (to C.L.); Canadian Institutes of Health Research (CIHR) grants MOP-286756 and FDN-154307 (to N.J.) and PJT-156086 (to C.L.K.); Canadian Cancer Society grant 705182 and 705799 (to L.G.), a Fonds de Recherche du Québec – Santé ( FRQS ) salary award (to C.L.K. and L.G.); NSERC RGPIN-2016-04911 (to C.L.K.); CFI Leaders Opportunity Fund 33902 (to C.L.K.); and Genome Canada Science Technology Innovation Center, McGill Genome Center, Compute Canada Resource Allocation Projects MJD-574-AC and WST-164-AB . Data analyses were enabled by computing and storage resources provided by Compute Canada and Calcul Québec. Mass spectrometry data was generated at the Network Biology Collaborative Center (NBCC), a facility supported by Canada Foundation for Innovation funding (Grant CFI 33474 ), the Ontario Government , Genome Canada , and Ontario Genomics ( OGI-139 ). N.J. is a member of the Penny Cole Laboratory and holds a Canada Research Chair (CRC) Tier 1 in Pediatric Oncology from CIHR; A.-C.G. is a CRC for Functional Proteomics. C.C.L.C. is supported by a fellowship from RI-MUHC sponsored by Toronto Dominion Bank and Alex's Lemonade Stand Foundation . B.A.G. is funded by NIH grants CA196539 and AI118891 , and the St. Jude Chromatin Consortium . E.I.C. is supported by CIHR ( PJT-159683 ), the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN-2016-05559 ), the Cancer Research Society , and the Garron Family Cancer Centre . S.M.M. is supported by a University of Toronto Open Fellowship. J.A.F. and C.C.G. were financed by the National Council for Scientific and Technological Development (CNPq)/Brazil and Coordination for the Improvement of Higher Education Personnel (CAPES)/Brazil Scholarship PDSE 88881.187783/2018-01 . Funding is acknowledged from the Crohn's and Colitis Foundation ( RFA 598467 to P.J.L.) and the NIH ( T32CA009140 to P.J.L.). Some figures were created using BioRender.com . Funding Information: This work was supported by a Large-Scale-Applied-Research-Project from Génome Quebec (GQ), Genome Canada, with the support of the Ontario Research Fund through funding provided by the Government of Ontario to N.J. C.L.K. and L.G. Additional support came from grant #25056 from the Cancer Research Society, GQ and Ministère de l’Économie et de l'Innovation du Québec. Additional funding support was provided by Fondation Charles-Bruneau and National Institutes of Health (NIH) grant P01-CA196539 (to N.J.), R01- R01CA255369 (to L.G.), R01-CA266978 and R35-GM138181 (to C.L.); Canadian Institutes of Health Research (CIHR) grants MOP-286756 and FDN-154307 (to N.J.) and PJT-156086 (to C.L.K.); Canadian Cancer Society grant 705182 and 705799 (to L.G.), a Fonds de Recherche du Québec – Santé (FRQS) salary award (to C.L.K. and L.G.); NSERC RGPIN-2016-04911 (to C.L.K.); CFI Leaders Opportunity Fund 33902 (to C.L.K.); and Genome Canada Science Technology Innovation Center, McGill Genome Center, Compute Canada Resource Allocation Projects MJD-574-AC and WST-164-AB. Data analyses were enabled by computing and storage resources provided by Compute Canada and Calcul Québec. Mass spectrometry data was generated at the Network Biology Collaborative Center (NBCC), a facility supported by Canada Foundation for Innovation funding (Grant CFI 33474), the Ontario Government, Genome Canada, and Ontario Genomics (OGI-139). N.J. is a member of the Penny Cole Laboratory and holds a Canada Research Chair (CRC) Tier 1 in Pediatric Oncology from CIHR; A.-C.G. is a CRC for Functional Proteomics. C.C.L.C. is supported by a fellowship from RI-MUHC sponsored by Toronto Dominion Bank and Alex's Lemonade Stand Foundation. B.A.G. is funded by NIH grants CA196539 and AI118891, and the St. Jude Chromatin Consortium. E.I.C. is supported by CIHR (PJT-159683), the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN-2016-05559), the Cancer Research Society, and the Garron Family Cancer Centre. S.M.M. is supported by a University of Toronto Open Fellowship. J.A.F. and C.C.G. were financed by the National Council for Scientific and Technological Development (CNPq)/Brazil and Coordination for the Improvement of Higher Education Personnel (CAPES)/Brazil Scholarship PDSE 88881.187783/2018-01. Funding is acknowledged from the Crohn's and Colitis Foundation (RFA 598467 to P.J.L.) and the NIH (T32CA009140 to P.J.L.). Some figures were created using BioRender.com. Conceived and designed the analysis: S.K. C.C.L.C. A.F.A. C.L.K. L.G. N.J. Collected the data: S.K. C.C.L.C. P.A. A.F.A. S.M.M. J.A.F. M.L. P.J.L. G.Y. C.R. M.Z. C.J.W. L.B. B.T. T.S.S. V.S. M.C. J.D. D.L. M.T.M. C.E.P. K.T. B.T.C. E.J.B. Contributed data or analysis tools: C.C.L.C. N.K. L.A. X.C. S.H. B.E. L.A.J.-M. D.F. A.-C.G. B.A.G. C.L. E.I.C. C.L.K. L.G. N.J. Performed the analysis: S.K. C.C.L.C. A.F.A. N.K. M.L. P.J.L. L.A. X.C. C.J.W. E.I.C. L.G. Other contributions: E.M.N. (biobank manager), C.C.G. (supervision). Wrote the paper: S.K. C.C.L.C. A.F.A. C.L.K. L.G. N.J. The authors declare no competing interests. Publisher Copyright: © 2023 Elsevier Inc.

PY - 2023/3/16

Y1 - 2023/3/16

N2 - Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated H3.3G34R/V/W knock-in mice and identified strikingly distinct developmental defects for each mutation. H3.3G34R-mutants exhibited progressive microcephaly and neurodegeneration, with abnormal accumulation of disease-associated microglia and concurrent neuronal depletion. G34R severely decreased H3K36me2 on the mutant H3.3 tail, impairing recruitment of DNA methyltransferase DNMT3A and its redistribution on chromatin. These changes were concurrent with sustained expression of complement and other innate immune genes possibly through loss of non-CG (CH) methylation and silencing of neuronal gene promoters through aberrant CG methylation. Complement expression in G34R brains may lead to neuroinflammation possibly accounting for progressive neurodegeneration. Our study reveals that H3.3G34-substitutions have differential impact on the epigenome, which underlie the diverse phenotypes observed, and uncovers potential roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating synaptic pruning and neuroinflammation in post-natal brains.

AB - Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated H3.3G34R/V/W knock-in mice and identified strikingly distinct developmental defects for each mutation. H3.3G34R-mutants exhibited progressive microcephaly and neurodegeneration, with abnormal accumulation of disease-associated microglia and concurrent neuronal depletion. G34R severely decreased H3K36me2 on the mutant H3.3 tail, impairing recruitment of DNA methyltransferase DNMT3A and its redistribution on chromatin. These changes were concurrent with sustained expression of complement and other innate immune genes possibly through loss of non-CG (CH) methylation and silencing of neuronal gene promoters through aberrant CG methylation. Complement expression in G34R brains may lead to neuroinflammation possibly accounting for progressive neurodegeneration. Our study reveals that H3.3G34-substitutions have differential impact on the epigenome, which underlie the diverse phenotypes observed, and uncovers potential roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating synaptic pruning and neuroinflammation in post-natal brains.

KW - CH methylation

KW - DNA methylation

KW - DNMT3A

KW - H3.3 G34R/V/W

KW - H3K36me2

KW - complement

KW - neurodegeneration

KW - neuroinflammation

KW - oncohistones

KW - synaptic pruning

UR - http://www.scopus.com/inward/record.url?scp=85149881631&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2023.02.023

DO - 10.1016/j.cell.2023.02.023

M3 - Article

C2 - 36931244

AN - SCOPUS:85149881631

SN - 0092-8674

VL - 186

SP - 1162-1178.e20

JO - Cell

JF - Cell

IS - 6

ER -

Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration

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