TY - JOUR
T1 - Histone gene replacement reveals a posttranscriptional role for H3K36 in maintaining metazoan transcriptome fidelity
AU - Meers, Michael P.
AU - Henriques, Telmo
AU - Lavender, Christopher A.
AU - McKay, Daniel J.
AU - Strahl, Brian D.
AU - Duronio, Robert J.
AU - Adelman, Karen
AU - Matera, A. Gregory
N1 - Funding Information:
We thank the UNC High Throughput Sequencing Facility for library preparation and general expertise, the TRiP at Harvard Medical School (NIH/NIGMS R01-GM084947) for providing transgenic RNAi fly stocks used in this study, members of the UNC Histone Replacement Consortium for critical review of data and figures, and Kayla Peck for help with plotting. MPM was supported by an NIH predoctoral fellowship, F31-CA177088. This work was supported by the NIH Epigenomics Roadmap Project, R01-DA036897 (to AGM, BDS and RJD), and by the Intramural Research Program of the NIH (Z01-ES101987), National Institute of Environmental Health Sciences (to KA).
Publisher Copyright:
© 2017, eLife Sciences Publications Ltd. All rights reserved.
PY - 2017/3/27
Y1 - 2017/3/27
N2 - Histone H3 lysine 36 methylation (H3K36me) is thought to participate in a host of cotranscriptional regulatory events. To study the function of this residue independent from the enzymes that modify it, we used a ‘histone replacement’ system in Drosophila to generate a nonmodifiable H3K36 lysine-to-arginine (H3K36R) mutant. We observed global dysregulation of mRNA levels in H3K36R animals that correlates with the incidence of H3K36me3. Similar to previous studies, we found that mutation of H3K36 also resulted in H4 hyperacetylation. However, neither cryptic transcription initiation, nor alternative pre-mRNA splicing, contributed to the observed changes in expression, in contrast with previously reported roles for H3K36me. Interestingly, knockdown of the RNA surveillance nuclease, Xrn1, and members of the CCR4-Not deadenylase complex, restored mRNA levels for a class of downregulated, H3K36me3-rich genes. We propose a post-transcriptional role for modification of replication-dependent H3K36 in the control of metazoan gene expression.
AB - Histone H3 lysine 36 methylation (H3K36me) is thought to participate in a host of cotranscriptional regulatory events. To study the function of this residue independent from the enzymes that modify it, we used a ‘histone replacement’ system in Drosophila to generate a nonmodifiable H3K36 lysine-to-arginine (H3K36R) mutant. We observed global dysregulation of mRNA levels in H3K36R animals that correlates with the incidence of H3K36me3. Similar to previous studies, we found that mutation of H3K36 also resulted in H4 hyperacetylation. However, neither cryptic transcription initiation, nor alternative pre-mRNA splicing, contributed to the observed changes in expression, in contrast with previously reported roles for H3K36me. Interestingly, knockdown of the RNA surveillance nuclease, Xrn1, and members of the CCR4-Not deadenylase complex, restored mRNA levels for a class of downregulated, H3K36me3-rich genes. We propose a post-transcriptional role for modification of replication-dependent H3K36 in the control of metazoan gene expression.
UR - http://www.scopus.com/inward/record.url?scp=85018263913&partnerID=8YFLogxK
U2 - 10.7554/eLife.23249
DO - 10.7554/eLife.23249
M3 - Article
C2 - 28346137
AN - SCOPUS:85018263913
VL - 6
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e23249
ER -