Human histone H1 variants impact splicing outcome by controlling RNA polymerase II elongation

Corina Pascal; Jonathan Zonszain; Ofir Hameiri; Chen Gargi-Levi; Galit Lev-Maor; Luna Tammer; Tamar Levy; Anan Tarabeih; Vanessa Rachel Roy; Stav Ben-Salmon; Liraz Elbaz; Mireille Eid; Tamar Hakim; Salima Abu Rabe'a; Nana Shalev; Albert Jordan; Eran Meshorer; Gil Ast

doi:10.1016/j.molcel.2023.10.003

Human histone H1 variants impact splicing outcome by controlling RNA polymerase II elongation

Corina Pascal, Jonathan Zonszain, Ofir Hameiri, Chen Gargi-Levi, Galit Lev-Maor, Luna Tammer, Tamar Levy, Anan Tarabeih, Vanessa Rachel Roy, Stav Ben-Salmon, Liraz Elbaz, Mireille Eid, Tamar Hakim, Salima Abu Rabe'a, Nana Shalev, Albert Jordan, Eran Meshorer, Gil Ast^*

^*Corresponding author for this work

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

4 Scopus citations

Abstract

Histones shape chromatin structure and the epigenetic landscape. H1, the most diverse histone in the human genome, has 11 variants. Due to the high structural similarity between the H1s, their unique functions in transferring information from the chromatin to mRNA-processing machineries have remained elusive. Here, we generated human cell lines lacking up to five H1 subtypes, allowing us to characterize the genomic binding profiles of six H1 variants. Most H1s bind to specific sites, and binding depends on multiple factors, including GC content. The highly expressed H1.2 has a high affinity for exons, whereas H1.3 binds intronic sequences. H1s are major splicing regulators, especially of exon skipping and intron retention events, through their effects on the elongation of RNA polymerase II (RNAPII). Thus, H1 variants determine splicing fate by modulating RNAPII elongation.

Original language	English
Pages (from-to)	3801-3817.e8
Journal	Molecular Cell
Volume	83
Issue number	21
DOIs	https://doi.org/10.1016/j.molcel.2023.10.003
State	Published - 2 Nov 2023

Funding

Funders	Funder number
Blavatnik Institute
Edmond J. Safra Bioinformatics Center
Israel Cancer Research Fund	PG-18-105, PG-20-104
Israel Cancer Research Fund
United States - Israel Binational Science Foundation	BSF 2017086
United States - Israel Binational Science Foundation
Harvard Medical School
Weizmann Institute of Science
Israel Science Foundation	ISF 2417/20, ISF 671/18, ISF 142/13
Israel Science Foundation
Tel Aviv University

Keywords

ChIP-seq
GC content
H1 histones
PRO-seq
RNA polymerase II elongation
RNA-seq
alternative splicing
exon skipping
intron retention

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10.1016/j.molcel.2023.10.003

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Pascal, C., Zonszain, J., Hameiri, O., Gargi-Levi, C., Lev-Maor, G., Tammer, L., Levy, T., Tarabeih, A., Roy, V. R., Ben-Salmon, S., Elbaz, L., Eid, M., Hakim, T., Abu Rabe'a, S., Shalev, N., Jordan, A., Meshorer, E., & Ast, G. (2023). Human histone H1 variants impact splicing outcome by controlling RNA polymerase II elongation. Molecular Cell, 83(21), 3801-3817.e8. https://doi.org/10.1016/j.molcel.2023.10.003

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title = "Human histone H1 variants impact splicing outcome by controlling RNA polymerase II elongation",

abstract = "Histones shape chromatin structure and the epigenetic landscape. H1, the most diverse histone in the human genome, has 11 variants. Due to the high structural similarity between the H1s, their unique functions in transferring information from the chromatin to mRNA-processing machineries have remained elusive. Here, we generated human cell lines lacking up to five H1 subtypes, allowing us to characterize the genomic binding profiles of six H1 variants. Most H1s bind to specific sites, and binding depends on multiple factors, including GC content. The highly expressed H1.2 has a high affinity for exons, whereas H1.3 binds intronic sequences. H1s are major splicing regulators, especially of exon skipping and intron retention events, through their effects on the elongation of RNA polymerase II (RNAPII). Thus, H1 variants determine splicing fate by modulating RNAPII elongation.",

keywords = "ChIP-seq, GC content, H1 histones, PRO-seq, RNA polymerase II elongation, RNA-seq, alternative splicing, exon skipping, intron retention",

author = "Corina Pascal and Jonathan Zonszain and Ofir Hameiri and Chen Gargi-Levi and Galit Lev-Maor and Luna Tammer and Tamar Levy and Anan Tarabeih and Roy, {Vanessa Rachel} and Stav Ben-Salmon and Liraz Elbaz and Mireille Eid and Tamar Hakim and {Abu Rabe'a}, Salima and Nana Shalev and Albert Jordan and Eran Meshorer and Gil Ast",

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year = "2023",

month = nov,

day = "2",

doi = "10.1016/j.molcel.2023.10.003",

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Pascal, C, Zonszain, J, Hameiri, O, Gargi-Levi, C, Lev-Maor, G, Tammer, L, Levy, T, Tarabeih, A, Roy, VR, Ben-Salmon, S, Elbaz, L, Eid, M, Hakim, T, Abu Rabe'a, S, Shalev, N, Jordan, A, Meshorer, E & Ast, G 2023, 'Human histone H1 variants impact splicing outcome by controlling RNA polymerase II elongation', Molecular Cell, vol. 83, no. 21, pp. 3801-3817.e8. https://doi.org/10.1016/j.molcel.2023.10.003

TY - JOUR

T1 - Human histone H1 variants impact splicing outcome by controlling RNA polymerase II elongation

AU - Pascal, Corina

AU - Zonszain, Jonathan

AU - Hameiri, Ofir

AU - Gargi-Levi, Chen

AU - Lev-Maor, Galit

AU - Tammer, Luna

AU - Levy, Tamar

AU - Tarabeih, Anan

AU - Roy, Vanessa Rachel

AU - Ben-Salmon, Stav

AU - Elbaz, Liraz

AU - Eid, Mireille

AU - Hakim, Tamar

AU - Abu Rabe'a, Salima

AU - Shalev, Nana

AU - Jordan, Albert

AU - Meshorer, Eran

AU - Ast, Gil

PY - 2023/11/2

Y1 - 2023/11/2

N2 - Histones shape chromatin structure and the epigenetic landscape. H1, the most diverse histone in the human genome, has 11 variants. Due to the high structural similarity between the H1s, their unique functions in transferring information from the chromatin to mRNA-processing machineries have remained elusive. Here, we generated human cell lines lacking up to five H1 subtypes, allowing us to characterize the genomic binding profiles of six H1 variants. Most H1s bind to specific sites, and binding depends on multiple factors, including GC content. The highly expressed H1.2 has a high affinity for exons, whereas H1.3 binds intronic sequences. H1s are major splicing regulators, especially of exon skipping and intron retention events, through their effects on the elongation of RNA polymerase II (RNAPII). Thus, H1 variants determine splicing fate by modulating RNAPII elongation.

AB - Histones shape chromatin structure and the epigenetic landscape. H1, the most diverse histone in the human genome, has 11 variants. Due to the high structural similarity between the H1s, their unique functions in transferring information from the chromatin to mRNA-processing machineries have remained elusive. Here, we generated human cell lines lacking up to five H1 subtypes, allowing us to characterize the genomic binding profiles of six H1 variants. Most H1s bind to specific sites, and binding depends on multiple factors, including GC content. The highly expressed H1.2 has a high affinity for exons, whereas H1.3 binds intronic sequences. H1s are major splicing regulators, especially of exon skipping and intron retention events, through their effects on the elongation of RNA polymerase II (RNAPII). Thus, H1 variants determine splicing fate by modulating RNAPII elongation.

KW - ChIP-seq

KW - GC content

KW - H1 histones

KW - PRO-seq

KW - RNA polymerase II elongation

KW - RNA-seq

KW - alternative splicing

KW - exon skipping

KW - intron retention

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AN - SCOPUS:85175420925

SN - 1097-2765

VL - 83

SP - 3801-3817.e8

JO - Molecular Cell

JF - Molecular Cell

IS - 21

ER -

Human histone H1 variants impact splicing outcome by controlling RNA polymerase II elongation

Abstract

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Keywords

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