TY - JOUR
T1 - Histone H1 regulates non-coding RNA turnover on chromatin in a m6A-dependent manner
AU - Fernández-Justel, José Miguel
AU - Santa-María, Cristina
AU - Martín-Vírgala, Sara
AU - Ramesh, Shreya
AU - Ferrera-Lagoa, Alberto
AU - Salinas-Pena, Mónica
AU - Isoler-Alcaraz, Javier
AU - Maslon, Magdalena
AU - Jordan, Albert
AU - Caceres, Javier F.
AU - Gómez, María
N1 - Funding Information:
We are indebted to Arthur Skoultchi and Encarna Martínez-Salas for reagents and advice, Ana Losada and Ana Cuadrado for help with RNAPII-ChIP, Luciana Gómez-Acuña for help on TT-seq, Sandra Benavente for advice in m6A-IP and FTO inhibition, and César Cobaleda for support on computational analysis. We are grateful to the SMOC and Genomic Services at CBMSO and Pepe Belio for art work. We also thank Wendy Bickmore, Andrew Wood, and Andrew Jackson for continuous support during M.G.’s sabbatical stay at the HGU and Ferran Azorín, Jordi Bernues, Victor Corces, Crisanto Gutierrez, and members of M.G. lab for critical reading of the manuscript. Work at the M.G. lab was supported by the Spanish Ministry of Sciences and Innovation (BFU2016-78849-P and PID2019-105949GB-I00, co-financed by the European Union FEDER funds), a CSIC grant (2019AEP004), and a Salvador de Madariaga mobility grant (PRX19/00293). J.M.F.-J. C.S.-M. and J.I.-A. were supported by the Spanish Ministry of Sciences and Innovation fellowships (BES-2014-070050, BES-2017-079897, and PRE2020-095071, respectively); S.M.-V. was supported by a predoctoral fellowship from the Spanish Ministry of Education and Universities (FPU18/04794); and M.S.-P. was supported by an AGAUR-FI predoctoral fellowship co-financed by Generalitat de Catalunya and the European Social Fund. A.J. was supported by the Spanish Ministry of Sciences and Innovation (BFU2017-82805-C2-1-P and PID2020-112783GB-C21) and J.F.C. by core funding to the MRC Human Genetics Unit from the Medical Research Council (UK). J.M.F.-J. C.S.-M. S.M.-V. S.R. A.F.-L. M.S.-P. and J.I.-A. performed experiments. J.M.F.-J. performed all computational analyses. J.M.F.-J. C.S.-M. and M.G. designed and analyzed the experiments. M.M.M. contributed to the TT-seq experimental design and analysis. M.G. conceived the project, analyzed experiments, and wrote the article. M.G. A.J. and J.F.C. secured the funding. All authors analyzed the data, discussed the results, and approved the final version of the manuscript. The authors declare no competing interests.
Funding Information:
We are indebted to Arthur Skoultchi and Encarna Martínez-Salas for reagents and advice, Ana Losada and Ana Cuadrado for help with RNAPII-ChIP, Luciana Gómez-Acuña for help on TT-seq, Sandra Benavente for advice in m6A-IP and FTO inhibition, and César Cobaleda for support on computational analysis. We are grateful to the SMOC and Genomic Services at CBMSO and Pepe Belio for art work. We also thank Wendy Bickmore, Andrew Wood, and Andrew Jackson for continuous support during M.G.’s sabbatical stay at the HGU and Ferran Azorín, Jordi Bernues, Victor Corces, Crisanto Gutierrez, and members of M.G. lab for critical reading of the manuscript. Work at the M.G. lab was supported by the Spanish Ministry of Sciences and Innovation ( BFU2016-78849-P and PID2019-105949GB-I00 , co-financed by the European Union FEDER funds), a CSIC grant ( 2019AEP004 ), and a Salvador de Madariaga mobility grant ( PRX19/00293 ). J.M.F.-J., C.S.-M., and J.I.-A. were supported by the Spanish Ministry of Sciences and Innovation fellowships ( BES-2014-070050 , BES-2017-079897 , and PRE2020-095071 , respectively); S.M.-V. was supported by a predoctoral fellowship from the Spanish Ministry of Education and Universities ( FPU18/04794 ); and M.S.-P. was supported by an AGAUR-FI predoctoral fellowship co-financed by Generalitat de Catalunya and the European Social Fund. A.J. was supported by the Spanish Ministry of Sciences and Innovation ( BFU2017-82805-C2-1-P and PID2020-112783GB-C21 ) and J.F.C. by core funding to the MRC Human Genetics Unit from the Medical Research Council (UK).
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/9/13
Y1 - 2022/9/13
N2 - Linker histones are highly abundant chromatin-associated proteins with well-established structural roles in chromatin and as general transcriptional repressors. In addition, it has been long proposed that histone H1 exerts context-specific effects on gene expression. Here, we identify a function of histone H1 in chromatin structure and transcription using a range of genomic approaches. In the absence of histone H1, there is an increase in the transcription of non-coding RNAs, together with reduced levels of m6A modification leading to their accumulation on chromatin and causing replication-transcription conflicts. This strongly suggests that histone H1 prevents non-coding RNA transcription and regulates non-coding transcript turnover on chromatin. Accordingly, altering the m6A RNA methylation pathway rescues the replicative phenotype of H1 loss. This work unveils unexpected regulatory roles of histone H1 on non-coding RNA turnover and m6A deposition, highlighting the intimate relationship between chromatin conformation, RNA metabolism, and DNA replication to maintain genome performance.
AB - Linker histones are highly abundant chromatin-associated proteins with well-established structural roles in chromatin and as general transcriptional repressors. In addition, it has been long proposed that histone H1 exerts context-specific effects on gene expression. Here, we identify a function of histone H1 in chromatin structure and transcription using a range of genomic approaches. In the absence of histone H1, there is an increase in the transcription of non-coding RNAs, together with reduced levels of m6A modification leading to their accumulation on chromatin and causing replication-transcription conflicts. This strongly suggests that histone H1 prevents non-coding RNA transcription and regulates non-coding transcript turnover on chromatin. Accordingly, altering the m6A RNA methylation pathway rescues the replicative phenotype of H1 loss. This work unveils unexpected regulatory roles of histone H1 on non-coding RNA turnover and m6A deposition, highlighting the intimate relationship between chromatin conformation, RNA metabolism, and DNA replication to maintain genome performance.
U2 - https://doi.org/10.1016/j.celrep.2022.111329
DO - https://doi.org/10.1016/j.celrep.2022.111329
M3 - Article
C2 - 36103831
SN - 2211-1247
VL - 40
JO - Cell Reports
JF - Cell Reports
IS - 11
ER -