Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity
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Abstract
Abstract Histone variants, which can be expressed outside of S-phase and deposited DNA synthesis-independently, provide long-term histone replacement in postmitotic cells, including neurons. Beyond replenishment, histone variants also play active roles in gene regulation by modulating chromatin states or enabling nucleosome turnover. Here, we uncover crucial roles for the histone H3 variant H3.3 in neuronal development. We find that newborn cortical excitatory neurons, which have only just completed replication-coupled deposition of canonical H3.1 and H3.2, substantially accumulate H3.3 immediately post mitosis. Co-deletion of H3.3-encoding genes H3f3a and H3f3b from newly postmitotic neurons abrogates H3.3 accumulation, markedly alters the histone posttranslational modification (PTM) landscape, and causes widespread disruptions to the establishment of the neuronal transcriptome. These changes coincide with developmental phenotypes in neuronal identities and axon projections. Thus, preexisting, replication-dependent histones are insufficient for establishing neuronal chromatin and transcriptome; de novo H3.3 is required. Stage-dependent deletion of H3f3a and H3f3b from (1) cycling neural progenitor cells, (2) neurons immediately post mitosis, or (3) several days later, reveals the first postmitotic days to be a critical window for de novo H3.3. After H3.3 accumulation within this developmental window, co-deletion of H3f3a and H3f3b does not lead to immediate H3.3 loss, but causes progressive H3.3 depletion over several months without widespread transcriptional disruptions or cellular phenotypes. Our study thus uncovers key developmental roles for de novo H3.3 in establishing neuronal chromatin, transcriptome, identity, and connectivity immediately post mitosis that are distinct from its role in maintaining total histone H3 levels over the neuronal lifespan. Significance DNA is packaged around histones into chromatin, which compacts the genome, but also restricts access to DNA. Gene transcription thus requires chromatin reorganization that is precisely regulated, including via variant forms of histones. Here, we find that during a critical developmental window for establishing postmitotic neuronal identity, newly generated cortical excitatory neurons substantially accumulate the histone H3 variant H3.3. Conditional deletion of H3.3-encoding genes from new neurons abrogates de novo H3.3 accumulation, and broadly disrupts neuronal histone modifications, gene expression, subtype identity, and axon projections. Thus, preexisting H3 histones are insufficient for establishing neuronal chromatin and transcriptome; de novo H3.3 is essential. This developmental requirement for H3.3 is distinct from H3.3 contribution to long-term maintenance of histones in mature neurons.
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Previous studies have shown the importance of histones in DNA damage response, senescence, brain aging, neuronal identity, and memory formation.
“Previous studies have shown the importance of histones in DNA damage response, senescence, brain aging, neuronal identity, and memory formation100–102,136–139.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [139]
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Cites
The Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041 · see citing works
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364 · see citing works
An integrated encyclopedia of DNA elements in the human genome
The ENCODE Project Consortium (2012) · Nature · doi:10.1038/nature11247 · Cited by 18,072 · see citing works
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174 · see citing works
ATAC-seq: a method for assaying chromatin accessibility genome-wide
Buenrostro, J. D., Wu, B., Chang, H. Y., & Greenleaf, W. J. (2015) · Current Protocols in Molecular Biology · doi:10.1002/0471142727.mb2129s109 · Cited by 3,289 · see citing works
CUT&Tag for efficient epigenomic profiling of small samples and single cells
Kaya-Okur, H. S., Wu, S. J., Codomo, C. A., Pledger, E. S., Bryson, T. D., Henikoff, J. G., Ahmad, K., & Henikoff, S. (2019) · Nature Communications · doi:10.1038/s41467-019-09982-5 · Cited by 2,187 · see citing works
Spatio-temporal transcriptome of the human brain
Kang, H. J., Kawasawa, Y. I., Cheng, F., Zhu, Y., Xu, X., Li, M., Sousa, A. M. M., Pletikos, M., Meyer, K. A., Sedmak, G., et al. (2011) · Nature · doi:10.1038/nature10523 · Cited by 2,084 · see citing works
Gorski, J. A., Talley, T., Qiu, M. S., Puelles, L., Rubenstein, J. L. R., & Jones, K. R. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-15-06309.2002 · Cited by 1,367 · see citing works
Distinct Factors Control Histone Variant H3.3 Localization at Specific Genomic Regions
Goldberg, A. D., Banaszynski, L. A., Noh, K., Lewis, P. W., Elsässer, S. J., Stadler, S. C., Dewell, S. B., Law, M. J., Guo, X., Li, X., et al. (2010) · Cell · doi:10.1016/j.cell.2010.01.003 · Cited by 1,281 · see citing works
Neuronal Subtype-Specific Genes that Control Corticospinal Motor Neuron Development In Vivo
Arlotta, P., Molyneaux, B. J., Chen, J., Inoue, J., Kominami, R., & Macklis, J. D. (2005) · Neuron · doi:10.1016/j.neuron.2004.12.036 · Cited by 1,157 · see citing works
Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex
Nowakowski, T. J., Bhaduri, A., Pollen, A. A., Alvarado, B., Mostajo-Radji, M. A., Di Lullo, E., Haeussler, M., Sandoval-Espinosa, C., Liu, S. J., Velmeshev, D., et al. (2017) · Science · doi:10.1126/science.aap8809 · Cited by 964 · see citing works
Histone exchange, chromatin structure and the regulation of transcription
Venkatesh, S., & Workman, J. L. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3941 · Cited by 940 · see citing works
Regulation of nucleosome dynamics by histone modifications
Zentner, G. E., & Henikoff, S. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2470 · Cited by 923 · cited 1× · see citing works
“Gene regulation is dependent on histone PTMs, including those decorating H3 (68).”
BackgroundTbr1 regulates differentiation of the preplate and layer 6
Hevner, R. F., Shi, L., Justice, N., Hsueh, Y.-P., Sheng, M., Smiga, S., Bulfone, A., Goffinet, A. M., Campagnoni, A. T., & Rubenstein, J. L. R. (2001) · Neuron · doi:10.1016/s0896-6273(01)00211-2 · Cited by 857 · see citing works
Jin, C., Zang, C., Wei, G., Cui, K., Peng, W., Zhao, K., & Felsenfeld, G. (2009) · Nature Genetics · doi:10.1038/ng.409 · Cited by 776 · see citing works
Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail
Marzluff, W. F., Wagner, E. J., & Duronio, R. J. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2438 · Cited by 768 · see citing works
Satb2 Is a Postmitotic Determinant for Upper-Layer Neuron Specification in the Neocortex
Britanova, O., de Juan Romero, C., Cheung, A., Kwan, K. Y., Schwark, M., Gyorgy, A., Vogel, T., Akopov, S., Mitkovski, M., Agoston, D., et al. (2008) · Neuron · doi:10.1016/j.neuron.2007.12.028 · Cited by 674 · see citing works
Self-citationSatb2 Regulates Callosal Projection Neuron Identity in the Developing Cerebral Cortex
Alcamo, E. A., Chirivella, L., Dautzenberg, M., Dobreva, G., Fariñas, I., Grosschedl, R., & McConnell, S. K. (2008) · Neuron · doi:10.1016/j.neuron.2007.12.012 · Cited by 658 · see citing works
Gerfen, C. R., Paletzki, R., & Heintz, N. (2013) · Neuron · doi:10.1016/j.neuron.2013.10.016 · Cited by 647 · see citing works
Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice
Goebbels, S., Bormuth, I., Bode, U., Hermanson, O., Schwab, M. H., & Nave, K. (2006) · genesis · doi:10.1002/dvg.20256 · Cited by 579 · see citing works
Nucleosome stability mediated by histone variants H3.3 and H2A.ZPreprint
Jin, C., & Felsenfeld, G. (2007) · Genes & Development · doi:10.1101/gad.1547707 · Cited by 544 · see citing works
Genome-scale profiling of histone H3.3 replacement patterns
Mito, Y., Henikoff, J. G., & Henikoff, S. (2005) · Nature Genetics · doi:10.1038/ng1637 · Cited by 511 · see citing works
Histone Variants and EpigeneticsPreprint
Henikoff, S., & Smith, M. M. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019364 · Cited by 414 · see citing works
The double face of the histone variant H3.3
Szenker‐Ravi, E., Ray-Gallet, D., & Almouzni, G. (2011) · Cell Research · doi:10.1038/cr.2011.14 · Cited by 392 · see citing works
The roles of histone variants in fine-tuning chromatin organization and function
Martire, S., & Banaszynski, L. A. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0262-8 · Cited by 392 · see citing works
Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells
Elsässer, S. J., Noh, K., Diaz, N. S., Allis, C. D., & Banaszynski, L. A. (2015) · Nature · doi:10.1038/nature14345 · Cited by 388 · see citing works
Transcriptional co-regulation of neuronal migration and laminar identity in the neocortex
Kwan, K. Y., Šestan, N., & Anton, E. S. (2012) · Development · doi:10.1242/dev.069963 · Cited by 388 · see citing works
Self-citationThe determination of projection neuron identity in the developing cerebral cortex
Leone, D. P., Srinivasan, K., Chen, B., Alcamo, E., & McConnell, S. K. (2008) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2008.05.006 · Cited by 382 · see citing works
Separation of basal histone synthesis from S-phase histone synthesis in dividing cells
Wu, R. S., & Bonner, W. M. (1981) · Cell · doi:10.1016/0092-8674(81)90415-3 · Cited by 360 · see citing works
Maze, I. S., Noh, K., Soshnev, A. A., & Allis, C. D. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3673 · Cited by 347 · see citing works
Chen, B., Wang, S. S., Hattox, A. M., Rayburn, H., Nelson, S. B., & McConnell, S. K. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804918105 · Cited by 336 · see citing works
Genome-Wide Views of Chromatin Structure
Rando, O. J., & Chang, H. Y. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.071107.134639 · Cited by 323 · see citing works
Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex
Bedogni, F., Hodge, R. D., Elsen, G. E., Nelson, B. R., Daza, R. A. M., Beyer, R. P., Bammler, T. K., Rubenstein, J. L. R., & Hevner, R. F. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002285107 · Cited by 322 · see citing works
Critical Role of Histone Turnover in Neuronal Transcription and Plasticity
Maze, I., Wenderski, W., Noh, K.-M., Bagot, R. C., Tzavaras, N., Purushothaman, I., Elsässer, S. J., Guo, Y., Ionete, C., Hurd, Y. L., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.06.014 · Cited by 306 · see citing works
SOX5 Controls the Sequential Generation of Distinct Corticofugal Neuron Subtypes
Lai, T. S., Jabaudon, D., Molyneaux, B. J., Azim, E., Arlotta, P., Menezes, J. R. L., & Macklis, J. D. (2008) · Neuron · doi:10.1016/j.neuron.2007.12.023 · Cited by 300 · see citing works
Banaszynski, L. A., Wen, D., Dewell, S. B., Whitcomb, S. J., Lin, M., Diaz, N. S., Elsässer, S. J., Chapgier, A. L. A., Goldberg, A. D., Canaani, E., et al. (2013) · Cell · doi:10.1016/j.cell.2013.08.061 · Cited by 280 · see citing works
Transient cortical circuits match spontaneous and sensory-driven activity during development
Molnár, Z., Luhmann, H. J., & Kanold, P. O. (2020) · Science · doi:10.1126/science.abb2153 · Cited by 280 · see citing works
Transcriptional Regulation of Cortical Neuron Migration by POU Domain Factors
McEvilly, R. J., de Diaz, M. O., Schonemann, M. D., Hooshmand, F., & Rosenfeld, M. G. (2002) · Science · doi:10.1126/science.1067132 · Cited by 271 · see citing works
Kwan, K. Y., Lam, M. M. S., Krsnik, Ž., Kawasawa, Y. I., Lefebvre, V., & Šestan, N. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806791105 · Cited by 271 · see citing works
Self-citationMcKenna, W. L., Betancourt, J., Larkin, K. A., Abrams, B., Guo, C., Rubenstein, J. L. R., & Chen, B. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4131-10.2011 · Cited by 252 · see citing works
H3.3 actively marks enhancers and primes gene transcription via opening higher-ordered chromatinPreprint
Chen, P., Zhao, J., Wang, Y., Wang, M., Long, H., Liang, D., Huang, L., Wen, Z., Li, W., Li, X., et al. (2013) · Genes & Development · doi:10.1101/gad.222174.113 · Cited by 248 · see citing works
Han, W., Kwan, K. Y., Shim, S., Lam, M. M. S., Shin, Y., Xu, X., Zhu, Y., Li, M., & Šestan, N. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016723108 · Cited by 206 · see citing works
Self-citationHistone H3.3 maintains genome integrity during mammalian developmentPreprint
Jang, C., Shibata, Y., Starmer, J., Yee, D., & Magnuson, T. (2015) · Genes & Development · doi:10.1101/gad.264150.115 · Cited by 201 · see citing works
Phosphorylation of histone H3.3 at serine 31 promotes p300 activity and enhancer acetylation
Martire, S., Gogate, A. A., Whitmill, A., Tafessu, A., Nguyen, J., Teng, Y., Tastemel, M., & Banaszynski, L. A. (2019) · Nature Genetics · doi:10.1038/s41588-019-0428-5 · Cited by 178 · see citing works
Chow, C.-M., Georgiou, A., Szutorisz, H., Silva, A. M. E., Pombo, A., Barahona, I., Dargelos, É., Canzonetta, C., & Dillon, N. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400366 · Cited by 168 · see citing works
Leone, D. P., Heavner, W. E., Ferenczi, E., Dobreva, G. D., Huguenard, J. R., Grosschedl, R., & McConnell, S. K. (2014) · Cerebral Cortex · doi:10.1093/cercor/bhu156 · Cited by 161 · see citing works
New functions for an old variant: no substitute for histone H3.3
Elsässer, S. J., Goldberg, A. D., & Allis, C. D. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.01.003 · Cited by 157 · see citing works
Piña, B., & Suau, P. (1987) · Developmental Biology · doi:10.1016/0012-1606(87)90426-x · Cited by 151 · see citing works
Kraushaar, D. C., Jin, W., Maunakea, A. K., Abraham, B. J., Ha, M., & Zhao, K. (2013) · Genome biology · doi:10.1186/gb-2013-14-10-r121 · Cited by 151 · see citing works
Histone Variants in Metazoan Development
Banaszynski, L. A., Allis, C. D., & Lewis, P. W. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.10.014 · Cited by 147 · see citing works
Histone H3.3 regulates dynamic chromatin states during spermatogenesis
Yuen, B. T. K., Bush, K. M., Barrilleaux, B. L., Cotterman, R. F., & Knoepfler, P. S. (2014) · Development · doi:10.1242/dev.106450 · Cited by 142 · see citing works
Tvardovskiy, A., Schwämmle, V., Kempf, S. J., Rogowska-Wrzesinska, A., & Jensen, O. N. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx696 · Cited by 132 · see citing works
Lin, C.-J., Conti, M., & Ramalho‐Santos, M. (2013) · Development · doi:10.1242/dev.095513 · Cited by 131 · see citing works
Comparative Analysis of Layer-Specific Genes in Mammalian Neocortex
Watakabe, A., Ichinohe, N., Ohsawa, S., Hashikawa, T., Komatsu, Y., Rockland, K. S., & Yamamori, T. (2006) · Cerebral Cortex · doi:10.1093/cercor/bhl102 · Cited by 131 · see citing works
Ayoub, A. E., Oh, S., Xie, Y., Leng, J., Cotney, J., Dominguez, M. H., Noonan, J. P., & Rakic, P. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112213108 · Cited by 129 · see citing works
Structures of human nucleosomes containing major histone H3 variants
Tachiwana, H., Osakabe, A., Shiga, T., Miya, Y., Kimurâ, H., Kagawa, W., & Kurumizaka, H. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444911014818 · Cited by 123 · see citing works
Contribution of the Two Genes Encoding Histone Variant H3.3 to Viability and Fertility in Mice
Tang, M. C. W., Jacobs, S. A., Mattiske, D. M., Soh, Y. M., Graham, A. N., Tran, A. H. V., Lim, S. L., Hudson, D. F., Kalitsis, P., O’Bryan, M. K., et al. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1004964 · Cited by 114 · see citing works
Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity
Darbandi, S. F., Schwartz, S. E. R., Qi, Q., Catta-Preta, R., Pai, E. L.-L., Mandell, J. D., Everitt, A., Rubin, A. N., Krasnoff, R., Katzman, S. J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.09.027 · Cited by 100 · see citing works
Enhancer regions show high histone H3.3 turnover that changes during differentiation
Deaton, A. M., Rodríguez, M. G., Mieczkowski, J., Tolstorukov, M. Y., Kundu, S., Sadreyev, R. I., Jansen, L. E. T., & Kingston, R. E. (2016) · eLife · doi:10.7554/elife.15316 · Cited by 96 · see citing works
Myogenic transcriptional activation of MyoD mediated by replication-independent histone deposition
Yang, J.-H., Song, Y., Seol, J.-H., Park, J. Y., Yang, Y.-J., Han, J., Youn, H., & Cho, E. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009830108 · Cited by 95 · see citing works
The Histone Variant H3.3 in Transcriptional Regulation and Human Disease
Shi, L., Wen, H., & Shi, X. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.11.019 · Cited by 95 · see citing works
Chromatin Regulation of Neuronal Maturation and Plasticity
Gallegos, D. A., Chan, U., Chen, L., & West, A. E. (2018) · Trends in Neurosciences · doi:10.1016/j.tins.2018.02.009 · Cited by 93 · see citing works
A Chromatin Accessibility Atlas of the Developing Human Telencephalon
Markenscoff-Papadimitriou, E., Whalen, S., Przytycki, P. F., Thomas, R., Binyameen, F., Nowakowski, T. J., Kriegstein, A. R., Sanders, S., State, M. W., Pollard, K. S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.002 · Cited by 87 · see citing works
Nucleosome Turnover Regulates Histone Methylation Patterns over the Genome
Chory, E. J., Calarco, J. P., Hathaway, N. A., Bell, O., Neel, D. S., & Crabtree, G. R. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.10.028 · Cited by 83 · see citing works
Routh, A. L., Head, S. R., Ordoukhanian, P. T., & Johnson, J. E. (2015) · Journal of Molecular Biology · doi:10.1016/j.jmb.2015.06.011 · Cited by 75 · see citing works
Goodwin, L. R., & Picketts, D. J. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.10.008 · Cited by 74 · see citing works
Distribution of histone H3.3 in hematopoietic cell lineages
Jin, C., & Felsenfeld, G. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509974103 · Cited by 73 · see citing works
Lyons, S. M., Cunningham, C. H., Welch, J. D., Groh, B. S., Guo, A. Y., Wei, B., Whitfield, M. L., Xiong, Y., & Marzluff, W. F. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw620 · Cited by 68 · see citing works
Histone variant H3.3 orchestrates neural stem cell differentiation in the developing brain
Xia, W., & Jiao, J. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.77 · Cited by 66 · see citing works
Liu, J., Wu, X., Zhang, H., Pfeifer, G. P., & Lü, Q. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.046 · Cited by 61 · see citing works
Regulation of neuronal connectivity in the mammalian brain by chromatin remodeling
Goodman, J. V., & Bonni, A. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.04.010 · Cited by 60 · see citing works
An Essential Role of Variant Histone H3.3 for Ectomesenchyme Potential of the Cranial Neural Crest
Cox, S. G., Kim, H., Garnett, A. T., Medeiros, D. M., An, W., & Crump, J. G. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002938 · Cited by 57 · see citing works
Transcriptional repression by FEZF2 restricts alternative identities of cortical projection neurons
Tsyporin, J., Tastad, D., Ma, X., Nehme, A., Finn, T. S., Huebner, L., Liu, G., Gallardo, D., Makhamreh, A. K., Roberts, J. M., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109269 · Cited by 50 · see citing works
Shi, L., Qalieh, A., Lam, M. M. S., Keil, J. M., & Kwan, K. Y. (2019) · Nature Communications · doi:10.1038/s41467-019-10411-w · Cited by 49 · see citing works
Self-citationGuo, P., Liu, Y., Geng, F., Daman, A. W., Liu, X., Zhong, L., Ravishankar, A., Lis, R., Durán, J. G. B., Itkin, T., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00795-7 · Cited by 47 · see citing works
Conditional allelic replacement applied to genes encoding the histone variant H3.3 in the mouse
Tang, M. C. W., Jacobs, S. A., Wong, L. H., & Mann, J. R. (2013) · genesis · doi:10.1002/dvg.22366 · Cited by 39 · see citing works
The Histone H3 Family and Its Deposition Pathways
Ray-Gallet, D., & Almouzni, G. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-8104-5_2 · Cited by 39 · see citing works
Keil, J. M., Doyle, D. Z., Qalieh, A., Lam, M. M. S., Funk, O. H., Qalieh, Y., Shi, L., Mohan, N., Sorel, A., & Kwan, K. Y. (2020) · Nature Communications · doi:10.1038/s41467-020-17551-4 · Cited by 33 · see citing works
Self-citationH3.3 turnover: A mechanism to poise chromatin for transcription, or a response to open chromatin?
Huang, C., & Zhu, B. (2014) · BioEssays · doi:10.1002/bies.201400005 · Cited by 30 · see citing works
Wenderski, W., & Maze, I. (2016) · Bioessays · doi:10.1002/bies.201500171 · Cited by 26 · see citing works
Chromatin remodeler Arid1a regulates subplate neuron identity and wiring of cortical connectivity
Doyle, D. Z., Lam, M. M. S., Qalieh, A., Qalieh, Y., Sorel, A., Funk, O. H., & Kwan, K. Y. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2100686118 · Cited by 24 · see citing works
Self-citationSnf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development
Alvarez-Saavedra, M., Yan, K., Repentigny, Y. D., Hashem, L. E., Nidhi, C., Sarwar, S., Yang, D., Ioshikhes, I. P., Kothary, R., Hirayama, T., et al. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00243 · Cited by 17 · see citing works
HuR stabilizes a polyadenylated form of replication‐dependent histone mRNAs under stress conditions
Ryu, I., Park, Y., Seo, J., Park, O. H., Ha, H., Nam, J., & Kim, Y. K. (2018) · The FASEB Journal · doi:10.1096/fj.201800431r · Cited by 6 · see citing works
Welch, J. D., Wei, B., Cunningham, C. H., et al. (2020) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/z4k4-jh72 · Cited by 2 · see citing works
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Dileep, V., Boix, C. A., Mathys, H., Marco, A., Welch, G. M., Meharena, H. S., Loon, A., Jeloka, R., Peng, Z., Bennett, D. A., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.038 · Cited by 130 · see citing works
Multifunctional histone variants in genome function
Wong, L. H., & Tremethick, D. J. (2024) · Nature Reviews Genetics · doi:10.1038/s41576-024-00759-1 · Cited by 53 · see citing works
Wu, D., Sun, J. K., & Chow, H. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002559 · Cited by 48 · see citing works
Knockout tales: the versatile roles of histone H3.3 in development and disease
Klein, R. H., & Knoepfler, P. S. (2023) · Epigenetics & Chromatin · doi:10.1186/s13072-023-00512-8 · Cited by 21 · see citing works
Zhang, X., Che, Y., Mao, L., Li, D., Deng, J., Guo, Y., Zhao, Q., Zhang, X., Wang, L., Gao, X., et al. (2023) · Genomics · doi:10.1016/j.ygeno.2023.110685 · Cited by 12 · see citing works
Johal, K. S., Cheema, M. S., & Stefanelli, G. (2023) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2205108 · Cited by 11 · see citing works
Abad, C., Robayo, M. C., Moreno, M. D. M. M., Bernardi, M. T., Otero, M. G., Kosanovic, C., Griswold, A. J., Pierson, T. M., Walz, K., & Young, J. I. (2024) · Translational Psychiatry · doi:10.1038/s41398-023-02678-x · Cited by 9 · see citing works
Liegro, C. M. D., Schiera, G., Schirò, G., & Liegro, I. D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311028 · Cited by 8 · see citing works
Layo-Carris, D. E., Lubin, E. E., Sangree, A. K., Clark, K. J., Durham, E. L., Gonzalez, E. M., Smith, S. M., Angireddy, R., Wang, X. M., Weiss, E., et al. (2024) · European Journal of Human Genetics · doi:10.1038/s41431-024-01610-1 · Cited by 8 · see citing works
Ash1l loss-of-function results in structural birth defects and altered cortical development
Toolan, K. P., McGrath, B., Brinkmeier, M. L., Camper, S. A., & Bielas, S. L. (2024) · Brain · doi:10.1093/brain/awae218 · Cited by 7 · see citing works
The many faces of H3.3 in regulating chromatin in embryonic stem cells and beyond
Cohen, L. R. Z., & Meshorer, E. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2024.03.003 · Cited by 7 · see citing works
Bryant, L. M., Sangree, A. K., Clark, K., & Bhoj, E. J. K. (2023) · Human Genetics · doi:10.1007/s00439-023-02536-2 · Cited by 7 · see citing works
Wang, Y., Zhang, S., Jia, H., Ji, F., & Jiao, J. (2025) · Advanced Science · doi:10.1002/advs.202414890 · Cited by 6 · see citing works
Sangree, A. K., Angireddy, R., Bhattarai, J. P., Wang, Y., Bryant, L. M., Waxman, E. A., Layo-Carris, D. E., Durham, E. L., Katsura, K. A., Lubin, E. E., et al. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-025-07175-x · Cited by 5 · see citing works
Porter, R. S., & Iwase, S. (2023) · Biochemical Society Transactions · doi:10.1042/bst20220889 · Cited by 5 · see citing works
Quinone reductase 2 reads H3 serotonylation to support human cortical neuron developmentPreprint
Chen, M., Yang, C., Li, X., Kong, L., Weekley, B. H., Wei, X., O’Chan, J. C., Sanctis, C. D., Almazan, V. F., Vinson, D. A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.17.712426 · Cited by 5 · see citing works
Qin, R., Zhang, Y., Yang, Y., Chen, J., Huang, L., Xü, W., Qin, Q., Liang, X., Lai, X., Huang, X., et al. (2024) · European journal of medical research · doi:10.1186/s40001-024-01989-z · Cited by 4 · see citing works
Histone H3.3 ensures cell proliferation and genomic stability during myeloid cell development
Chauhan, S., Kudoh, F., Dey, A., & Ozato, K. (2026) · iScience · doi:10.1016/j.isci.2026.116501 · Cited by 2 · see citing works
Li, J., Tanzillo, A. F., Pizzirusso, G., Caccavano, A., Chittajallu, R., Sohn, M., Abebe, D. T., Zhang, Y., Pelkey, K. A., Dale, R., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-69248-9 · Cited by 2 · see citing works
Histone variants: expanding the epigenetic potential of neurons one amino acid at a time
Lukasak, B. J., & Korb, E. (2025) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2025.03.015 · Cited by 2 · see citing works
Sleep Deprivation and Neuronal Hyperexcitation Share Transcriptomic Signatures
Chatzigiannis, M. M., Hagihara, H., & Miyakawa, T. (2026) · Neuropsychopharmacology Reports · doi:10.1002/npr2.70150 · Cited by 1 · see citing works
Spatially resolved mapping of histones reveals selective neuronal response in Rett syndrome
Schäfer, F., Rocco, G. D., Völker-Albert, M. C., Forné, I., Landsberger, N., Imhof, A., & Lahiri, S. (2026) · FEBS Journal · doi:10.1111/febs.70534 · Cited by 1 · see citing works
A vector system encoding histone H3 mutants facilitates manipulations of the neuronal epigenome
Warren, S., Xiong, S., Robles-Magallanes, D., & Baizabal, J. (2024) · Scientific Reports · doi:10.1038/s41598-024-74270-2 · Cited by 1 · see citing works
Bouchereau, W., Chenane, L., Weiss‐Gayet, M., Lessard, L., Cardona, Y., Mounier, R., Gallay, L., Allenbach, Y., Benvéniste, O., Corpet, A., et al. (2026) · NAR Molecular Medicine · doi:10.1093/narmme/ugag022 · Cited by 1 · see citing works
H3.3 De Novo Mutations Alter Lysine 36 Methylation via Distinct MechanismsPreprint
Morcos, S. M., Sarvan, S., Saettone, A., Wong, C. J., Vo, S., Milo, A., Bayoumy, O. H., Angireddy, R., Burke, G. L., Greenblatt, J., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.09.674984 · Cited by 1 · see citing works
Sandoval, C. H., Borchers, C., Osburn, K., Boyd, B., & Aoki, S. T. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.10.648275
Young, D. L., Aguilan, J. T., Cutler, R. R., Stransky, S., DeAngelo, J. D., Roth, J. S., Małachowska, B., Vercellino, J., Bell, B. I., Shechter, D., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.11.647869
Histone H3 availability is more important for development than H3.2 versus H3.3 subtype identityPreprint
McPherson, J.-M. E., Sykes, C., Grossmann, L. C., Hill, C. H., Leatham-Jensen, M. P., Duronio, R. J., & McKay, D. A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.09.704946
HIRA-mediated H3.3 deposition preserves hepatocyte cell identity during liver agingPreprint
Arnold, R., Teneche, M. G., Lei, X., Gandhi, A., Shi, C. H., Proulx, J. M., Rajesh, A., Havas, A. P., Su, S., Sethiya, A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.09.710643
Evidence for coordinate CTCF and histone H3.3 activities in K27M diffuse midline gliomas
Klein, R. H., Yee, J. Q., & Knoepfler, P. S. (2026) · Acta Neuropathologica Communications · doi:10.1186/s40478-026-02290-2
HIRA-mediated H3.3 deposition preserves hepatocyte cell identity during liver agingPreprint
Adams, P. D., Arnold, R., Teneche, M. G., Lei, X., Gandhi, A., Shi, C., Proulx, J., Rajesh, A., Havas, A. P., Su, S., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-9261217/v1
Glioblastoma stem cell growth requires DOT1L-MED23 control of enhancer accessibility
Assaf, S., Bozek, D. A., Heemskerk, K., Banks, A., MacLeod, G., Bahia, R. K., Cutts, E., Johnston, M. J. G., Cseh, O., Angers, S., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117647
Young, D. L., Stransky, S., Molero, M. G., Yamashita, E., Pande, S., Kumar, V., Singh, S., Aguilan, J. T., Cutler, R., Koba, W., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117785
Developmental rewiring of EHMT1 function during human cortical neurogenesisPreprint
Kasliwal, K., Chatterjee, K., Bocchi, V. D., Mahmood, S. R., Uyehara, C. M., Marchese, W., Laguillo-Diego, A., Goetzler, E., Theis, G., Minotti, A. P., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.09.757098
A Novel Sparse Cellular Labeling System with Tunable Gradients and Long‐Term Stability
Tang, X., Hou, Z., Lu, L., Song, Y., Chai, C., Li, L., Shen, Y., Wang, S., Zhao, Y., Zeng, J., et al. (2026) · Advanced Science · doi:10.1002/advs.77438
- Authors
- Funk, O. H., Qalieh, Y., Doyle, D. Z., Lam, M. M., & Kwan, K. Y.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Kwan, Kenneth Y.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2022-08-05
- Volume
- 119
- Issue
- 32
- Pages
- e2116956119-e2116956119
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC9371731
- OpenAlex
- W4291708389
- Cited by
- 33
- References
- 83
- Citations by year
- 2026: 12 · 2025: 5 · 2024: 8 · 2023: 8
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01 NS097525, F31 NS110206)
- HHS | NIH | National Institute of General Medical Sciences (T32 GM007544)
- Brain Research Foundation (BRFSG-2016-04)
- March of Dimes Foundation (5-FY15-33)
- Simons Foundation (402213)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- histone H3.3, histone variants, postmitotic neurons, cortical excitatory neurons, neuronal development, neuronal identity, neuronal transcriptome, H3F3A, H3F3B, histone modifications, axonal projections, neural progenitor cells
- MeSH terms
- Animals, Cerebral Cortex, Chromatin, Histones, Mitosis, Neurons, Nucleosomes, Mice, Neurogenesis, Transcriptome
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