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bioRxiv · 10.1101/2025.01.22.634368

Differential regulation of histone H1 subtypes by N6-methyladenosine RNA methylation.

Garcia-Gomis, D.·Lopez-Gomez, J.·Andres, M.·Serna-Pujol, N.·Ponte, I.·Jordan, A.·Roque, A.
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Abstract

Histone H1 is involved in the regulation of chromatin structure and gene expression. Up to seven H1 subtypes or variants are expressed in human somatic cells. The H1 complement, defined as the subtype composition and proportions in each cell, is highly variable depending on the cell type, cell cycle stage, developmental context, and several diseases such as cancer. This variability results from the combined action of multiple regulatory processes. Epitranscriptomic modifications have emerged as a new regulatory layer capable of controlling all aspects of mRNA metabolism. In this work, we examined the role of the most prevalent mRNA modification, N6 methyladenosine (m6A), in the regulation of H1 subtypes. MeRIP-seq showed that H1-0 and H1-4 are enriched in m6A, whereas H1-2 displays intermediate levels of this mark. Integration of the functional studies involving m6A inhibition and partial depletion of these m6A readers led us to propose the first model of the differential regulation of H1 subtypes by m6A. In this model, m6A promotes the degradation of H1-0 mRNA mediated by YTHDF2, while it enhances the stability of H1-2 mRNA through IGF2BP1 binding and its translation by the combined action of IGF2BP1 and hnRNPD. In the case of H1-4, m6A promotes its transcription and stimulates its translation via hnRNPD binding. These findings suggest that m6A participates in the subtype-specific regulation of H1 variants, adding another layer to their complex regulation and contributing to the variability of the H1 complement in cancer. KeypointsO_LIHistone transcripts have different levels of m6A. C_LIO_LIWe analyzed the function of m6A in H1-0, H1-2, and H1-4 and identified its readers. C_LIO_LIWe propose the first model of the role of m6A in the subtype-specific regulation of histone H1. C_LI

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Garcia-Gomis, D., Lopez-Gomez, J., Andres, M., Serna-Pujol, N., Ponte, I., Jordan, A., Roque, A.. 2025-01-24. Differential regulation of histone H1 subtypes by N6-methyladenosine RNA methylation.. https://doi.org/10.1101/2025.01.22.634368

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