Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation

Matías Alvarez-Saavedra; Yves De Repentigny; Pamela S. Lagali; Edupuganti V.S. Raghu Ram; Keqin Yan; Emile Hashem; Danton Ivanochko; Michael S. Huh; Doo Yang; Alan J. Mears; Matthew A.M. Todd; Chelsea P. Corcoran; Erin A. Bassett; Nicholas J.A. Tokarew; Juraj Kokavec; Romit Majumder; Ilya Ioshikhes; Valerie A. Wallace; Rashmi Kothary; Eran Meshorer; Tomas Stopka; Arthur I. Skoultchi; David J. Picketts

doi:10.1038/ncomms5181

Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation

Matías Alvarez-Saavedra, Yves De Repentigny, Pamela S. Lagali, Edupuganti V.S. Raghu Ram, Keqin Yan, Emile Hashem, Danton Ivanochko, Michael S. Huh, Doo Yang, Alan J. Mears, Matthew A.M. Todd, Chelsea P. Corcoran, Erin A. Bassett, Nicholas J.A. Tokarew, Juraj Kokavec, Romit Majumder, Ilya Ioshikhes, Valerie A. Wallace, Rashmi Kothary, Eran MeshorerTomas Stopka, Arthur I. Skoultchi, David J. Picketts^*

^*Corresponding author for this work

Department of Genetics

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

61 Scopus citations

Abstract

Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation.

Original language	English
Article number	4181
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5181
State	Published - 20 Jun 2014

Bibliographical note

Funding Information:
We are grateful to Dr Diane Lagace and Mirela Hasu at the University of Ottawa Behavioral Core for assistance with behavioural experiments and expert discussions. We thank Dr Alexandra Joyner for pan-Engrailed antibodies. M.A.-S. thanks D.J.P. for funding and Dr Peter Becker for expert discussions. This work was funded by operating grants GACR P305/12/1033 and UNCE 20421 to T.S.; NIH grant R01 CA079057 to A.I.S.; and CIHR grants MOP97764 and MOP84412 to D.J.P.

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Alvarez-Saavedra, M., De Repentigny, Y., Lagali, P. S., Raghu Ram, E. V. S., Yan, K., Hashem, E., Ivanochko, D., Huh, M. S., Yang, D., Mears, A. J., Todd, M. A. M., Corcoran, C. P., Bassett, E. A., Tokarew, N. J. A., Kokavec, J., Majumder, R., Ioshikhes, I., Wallace, V. A., Kothary, R., ... Picketts, D. J. (2014). Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation. Nature Communications, 5, Article 4181. https://doi.org/10.1038/ncomms5181

@article{93c6918f55254b38a65d68aea68d8bc7,

title = "Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation",

abstract = "Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation.",

author = "Mat{\'i}as Alvarez-Saavedra and {De Repentigny}, Yves and Lagali, {Pamela S.} and {Raghu Ram}, {Edupuganti V.S.} and Keqin Yan and Emile Hashem and Danton Ivanochko and Huh, {Michael S.} and Doo Yang and Mears, {Alan J.} and Todd, {Matthew A.M.} and Corcoran, {Chelsea P.} and Bassett, {Erin A.} and Tokarew, {Nicholas J.A.} and Juraj Kokavec and Romit Majumder and Ilya Ioshikhes and Wallace, {Valerie A.} and Rashmi Kothary and Eran Meshorer and Tomas Stopka and Skoultchi, {Arthur I.} and Picketts, {David J.}",

note = "Funding Information: We are grateful to Dr Diane Lagace and Mirela Hasu at the University of Ottawa Behavioral Core for assistance with behavioural experiments and expert discussions. We thank Dr Alexandra Joyner for pan-Engrailed antibodies. M.A.-S. thanks D.J.P. for funding and Dr Peter Becker for expert discussions. This work was funded by operating grants GACR P305/12/1033 and UNCE 20421 to T.S.; NIH grant R01 CA079057 to A.I.S.; and CIHR grants MOP97764 and MOP84412 to D.J.P.",

year = "2014",

month = jun,

day = "20",

doi = "10.1038/ncomms5181",

language = "אנגלית",

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journal = "Nature Communications",

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Alvarez-Saavedra, M, De Repentigny, Y, Lagali, PS, Raghu Ram, EVS, Yan, K, Hashem, E, Ivanochko, D, Huh, MS, Yang, D, Mears, AJ, Todd, MAM, Corcoran, CP, Bassett, EA, Tokarew, NJA, Kokavec, J, Majumder, R, Ioshikhes, I, Wallace, VA, Kothary, R, Meshorer, E, Stopka, T, Skoultchi, AI & Picketts, DJ 2014, 'Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation', Nature Communications, vol. 5, 4181. https://doi.org/10.1038/ncomms5181

TY - JOUR

T1 - Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation

AU - Alvarez-Saavedra, Matías

AU - De Repentigny, Yves

AU - Lagali, Pamela S.

AU - Raghu Ram, Edupuganti V.S.

AU - Yan, Keqin

AU - Hashem, Emile

AU - Ivanochko, Danton

AU - Huh, Michael S.

AU - Yang, Doo

AU - Mears, Alan J.

AU - Todd, Matthew A.M.

AU - Corcoran, Chelsea P.

AU - Bassett, Erin A.

AU - Tokarew, Nicholas J.A.

AU - Kokavec, Juraj

AU - Majumder, Romit

AU - Ioshikhes, Ilya

AU - Wallace, Valerie A.

AU - Kothary, Rashmi

AU - Meshorer, Eran

AU - Stopka, Tomas

AU - Skoultchi, Arthur I.

AU - Picketts, David J.

N1 - Funding Information: We are grateful to Dr Diane Lagace and Mirela Hasu at the University of Ottawa Behavioral Core for assistance with behavioural experiments and expert discussions. We thank Dr Alexandra Joyner for pan-Engrailed antibodies. M.A.-S. thanks D.J.P. for funding and Dr Peter Becker for expert discussions. This work was funded by operating grants GACR P305/12/1033 and UNCE 20421 to T.S.; NIH grant R01 CA079057 to A.I.S.; and CIHR grants MOP97764 and MOP84412 to D.J.P.

PY - 2014/6/20

Y1 - 2014/6/20

N2 - Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation.

AB - Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation.

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JO - Nature Communications

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Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation

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