Global H3.3 dynamic deposition defines its bimodal role in cell fate transition

Hai Tong Fang; Chadi A. El Farran; Qiao Rui Xing; Li Feng Zhang; Hu Li; Bing Lim; Yuin Han Loh

doi:10.1038/s41467-018-03904-7

Global H3.3 dynamic deposition defines its bimodal role in cell fate transition

Hai Tong Fang, Chadi A. El Farran, Qiao Rui Xing, Li Feng Zhang, Hu Li, Bing Lim, Yuin Han Loh

Pharmacology

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

18 Scopus citations

Abstract

H3.3 is a histone variant, which is deposited on genebodies and regulatory elements, by Hira, marking active transcription. Moreover, H3.3 is deposited on heterochromatin by Atrx/Daxx complex. The exact role of H3.3 in cell fate transition remains elusive. Here, we investigate the dynamic changes in the deposition of the histone variant H3.3 during cellular reprogramming. H3.3 maintains the identities of the parental cells during reprogramming as its removal at early time-point enhances the efficiency of the process. We find that H3.3 plays a similar role in transdifferentiation to hematopoietic progenitors and neuronal differentiation from embryonic stem cells. Contrastingly, H3.3 deposition on genes associated with the newly reprogrammed lineage is essential as its depletion at the later phase abolishes the process. Mechanistically, H3.3 deposition by Hira, and its K4 and K36 modifications are central to the role of H3.3 in cell fate conversion. Finally, H3.3 safeguards fibroblast lineage by regulating Mapk cascade and collagen synthesis.

Original language	English (US)
Article number	1537
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03904-7
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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title = "Global H3.3 dynamic deposition defines its bimodal role in cell fate transition",

abstract = "H3.3 is a histone variant, which is deposited on genebodies and regulatory elements, by Hira, marking active transcription. Moreover, H3.3 is deposited on heterochromatin by Atrx/Daxx complex. The exact role of H3.3 in cell fate transition remains elusive. Here, we investigate the dynamic changes in the deposition of the histone variant H3.3 during cellular reprogramming. H3.3 maintains the identities of the parental cells during reprogramming as its removal at early time-point enhances the efficiency of the process. We find that H3.3 plays a similar role in transdifferentiation to hematopoietic progenitors and neuronal differentiation from embryonic stem cells. Contrastingly, H3.3 deposition on genes associated with the newly reprogrammed lineage is essential as its depletion at the later phase abolishes the process. Mechanistically, H3.3 deposition by Hira, and its K4 and K36 modifications are central to the role of H3.3 in cell fate conversion. Finally, H3.3 safeguards fibroblast lineage by regulating Mapk cascade and collagen synthesis.",

author = "Fang, {Hai Tong} and {El Farran}, {Chadi A.} and Xing, {Qiao Rui} and Zhang, {Li Feng} and Hu Li and Bing Lim and Loh, {Yuin Han}",

note = "Funding Information: We thank Tushar Warrier and Yu Tao for technical assistances and providing insights during the writing of the manuscript. H.L. is supported by the funding from the National Institutes of Health (R01CA196631), (R01CA208517) and by a grant from Paul F. Glenn Foundation. Y.-H.L. is supported by the (A*Star Investigatorship research award— 1437a00116), (JCO Development Programme Grant—1534n00153) and (NRF Investi-gatorship grant). Y.-H.L. and L.-F.Z. are supported by the Singapore National Research Foundation under its Cooperative Basic Research Grant administered by the Singapore Ministry of Health{\textquoteright}s National Medical Research Council (NMRC/CBRG/0092/2015). We are grateful to the Biomedical Research Council, Agency for Science, Technology and Research, Singapore for research funding. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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doi = "10.1038/s41467-018-03904-7",

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AU - Fang, Hai Tong

AU - El Farran, Chadi A.

AU - Xing, Qiao Rui

AU - Zhang, Li Feng

AU - Li, Hu

AU - Lim, Bing

AU - Loh, Yuin Han

N1 - Funding Information: We thank Tushar Warrier and Yu Tao for technical assistances and providing insights during the writing of the manuscript. H.L. is supported by the funding from the National Institutes of Health (R01CA196631), (R01CA208517) and by a grant from Paul F. Glenn Foundation. Y.-H.L. is supported by the (A*Star Investigatorship research award— 1437a00116), (JCO Development Programme Grant—1534n00153) and (NRF Investi-gatorship grant). Y.-H.L. and L.-F.Z. are supported by the Singapore National Research Foundation under its Cooperative Basic Research Grant administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC/CBRG/0092/2015). We are grateful to the Biomedical Research Council, Agency for Science, Technology and Research, Singapore for research funding. Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

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N2 - H3.3 is a histone variant, which is deposited on genebodies and regulatory elements, by Hira, marking active transcription. Moreover, H3.3 is deposited on heterochromatin by Atrx/Daxx complex. The exact role of H3.3 in cell fate transition remains elusive. Here, we investigate the dynamic changes in the deposition of the histone variant H3.3 during cellular reprogramming. H3.3 maintains the identities of the parental cells during reprogramming as its removal at early time-point enhances the efficiency of the process. We find that H3.3 plays a similar role in transdifferentiation to hematopoietic progenitors and neuronal differentiation from embryonic stem cells. Contrastingly, H3.3 deposition on genes associated with the newly reprogrammed lineage is essential as its depletion at the later phase abolishes the process. Mechanistically, H3.3 deposition by Hira, and its K4 and K36 modifications are central to the role of H3.3 in cell fate conversion. Finally, H3.3 safeguards fibroblast lineage by regulating Mapk cascade and collagen synthesis.

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Global H3.3 dynamic deposition defines its bimodal role in cell fate transition

Abstract

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