Nascent transcription profiling identifies H3K36 methylation as a custodian of the somatic transcriptome
Abstract
Faithful gene expression not only requires activation of productive transcription units, but also suppression of aberrant initiation within or between gene bodies. In Saccharomyces, Set2-mediated H3 lysine-36 methylation (H3K36me) recruits a deacetylase complex that removes acetylation deposited behind elongating RNA polymerase II, preventing cryptic initiation. Whether metazoans require Set2 or the K36 residue itself for this function has been difficult to test. Here, we combined PRO-seq, RNA-seq, and chromatin profiling in Drosophila wing imaginal discs to define individual contributions of Set2, H3.2K36 and H3.3K36 to transcriptome fidelity. Intragenic initiation events are abundant but largely unresponsive to loss of K36 methylation. Aberrant initiation instead concentrates in repetitive, extragenic chromatin, co-marked by H3K9me2/3 and H3K36me2 but depleted of H3K36me3, a dual heterochromatin signature that is also conserved in mammals. Within this compartment, piRNA clusters, germline-restricted genes, and LTR and LINE retrotransposons are aberrantly activated in somatic tissue. A K36R substitution in H3.2, but not in H3.3, derepresses these loci to a far greater extent than deleting Set2, which retains K36me2 but cannot deposit K36me3. Thus, metazoan H3K36 safeguards the somatic transcriptome principally within heterochromatin, rather than within gene bodies.
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BibTeX
@misc{sultana2026nascent,
title = {{Nascent transcription profiling identifies H3K36 methylation as a custodian of the somatic transcriptome}},
author = {Hina Sultana and Vasudha Vandadi and Harmony R. Salzler and Apoorva Baluapuri and Darshan Ponkiya and Alexis K. Hirth and Grace C. Vernesoni and Seth R. Goldman and Karen Adelman and A. Gregory Matera},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.25.761580},
url = {https://www.biorxiv.org/content/10.64898/2026.10.25.761580v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Nascent transcription profiling identifies H3K36 methylation as a custodian of the somatic transcriptome
AU - Hina Sultana
AU - Vasudha Vandadi
AU - Harmony R. Salzler
AU - Apoorva Baluapuri
AU - Darshan Ponkiya
AU - Alexis K. Hirth
AU - Grace C. Vernesoni
AU - Seth R. Goldman
AU - Karen Adelman
AU - A. Gregory Matera
PY - 2026
DA - 2026/10/25
PB - bioRxiv
DO - 10.64898/2026.10.25.761580
UR - https://www.biorxiv.org/content/10.64898/2026.10.25.761580v1
AB - Faithful gene expression not only requires activation of productive transcription units, but also suppression of aberrant initiation within or between gene bodies. In Saccharomyces, Set2-mediated H3 lysine-36 methylation (H3K36me) recruits a deacetylase complex that removes acetylation deposited behind elongating RNA polymerase II, preventing cryptic initiation. Whether metazoans require Set2 or the K36 residue itself for this function has been difficult to test. Here, we combined PRO-seq, RNA-seq, and chromatin profiling in Drosophila wing imaginal discs to define individual contributions of Set2, H3.2K36 and H3.3K36 to transcriptome fidelity. Intragenic initiation events are abundant but largely unresponsive to loss of K36 methylation. Aberrant initiation instead concentrates in repetitive, extragenic chromatin, co-marked by H3K9me2/3 and H3K36me2 but depleted of H3K36me3, a dual heterochromatin signature that is also conserved in mammals. Within this compartment, piRNA clusters, germline-restricted genes, and LTR and LINE retrotransposons are aberrantly activated in somatic tissue. A K36R substitution in H3.2, but not in H3.3, derepresses these loci to a far greater extent than deleting Set2, which retains K36me2 but cannot deposit K36me3. Thus, metazoan H3K36 safeguards the somatic transcriptome principally within heterochromatin, rather than within gene bodies.
SN - 2692-8205
ER -