Biology subjects

DeAngelo, J. D.

Publications and source records attributed to DeAngelo, J. D..

3 recordsLinked to original sources

bioRxiv2025

PRMT5 activity sustains histone production to maintain genome integrity

Histone proteins package DNA into nucleosomes, forming chromatin and thereby safeguarding genome integrity. Proper histone expression is essential for cell proliferation and chromatin organization, yet the upstream regulators of histone supply remain incompletely understood. PRMT5--a cell essential type II protein arginine methyltransferase frequently overexpressed in cancer--catalyzes symmetric dimethylation of arginine residues. Using time-resolved nascent transcriptional profiling, quantitative proteomics, and imaging, we show that PRMT5 activity is required to sustain histone transcription and histone protein synthesis during S phase. PRMT5 inhibition or knockdown leads to rapid histone mRNA depletion, loss of histone proteins, and accumulation of replicationassociated nuclear abnormalities. We further show that soluble histone H4 accumulates at histone locus bodies (HLBs) upon PRMT5 inhibition, and that PRMT5-substrate H4 Arginine 3 mutants localize more robustly to HLBs than do wildtype H4. These findings support a model in which PRMT5-mediated methylation of histone H4 regulates histone transcription. Our findings establish PRMT5 as a central coordinator of histone homeostasis and provide a mechanistic rationale for its essential role in proliferating cells.

cell biology↗

bioRxiv2024

Productive mRNA Chromatin Escape is Promoted by PRMT5 Methylation of SNRPB

Protein Arginine Methyltransferase 5 (PRMT5) regulates RNA splicing and transcription by symmetric dimethylation of arginine residues (Rme2s/SDMA) in many RNA binding proteins. However, the mechanism by which PRMT5 couples splicing to transcriptional output is unknown. Here, we demonstrate that a major function of PRMT5 activity is to promote chromatin escape of a novel, large class of mRNAs that we term Genomically Retained Incompletely Processed Polyadenylated Transcripts (GRIPPs). Using nascent and total transcriptomics, spike-in controlled fractionated cell transcriptomics, and total and fractionated cell proteomics, we show that PRMT5 inhibition and knockdown of the PRMT5 SNRP (Sm protein) adapter protein pICln (CLNS1A) --but not type I PRMT inhibition--leads to gross detention of mRNA, SNRPB, and SNRPD3 proteins on chromatin. Compared to most transcripts, these chromatin-trapped polyadenylated RNA transcripts have more introns, are spliced slower, and are enriched in detained introns. Using a combination of PRMT5 inhibition and inducible isogenic wildtype and arginine-mutant SNRPB, we show that arginine methylation of these snRNPs is critical for mediating their homeostatic chromatin and RNA interactions. Overall, we conclude that a major role for PRMT5 is in controlling transcript processing and splicing completion to promote chromatin escape and subsequent nuclear export.

molecular biology↗

bioRxiv2024

EXOSC4 is recruited by histone H3 co-modified with K9me3 and acetylations to surveil non-coding transcription

Histones are hyper modified proteins that regulate chromatin accessibility and DNA readout. Co-existing post-translational modifications (PTMs) on histones affect interaction affinities of chromatin-associated proteins in ways that are still mostly unexplored. Here, we focus on the biological role of a specific histone code made of two PTMs with supposedly opposing biological functions, i.e. H3K9me3 marker of constitutive heterochromatin and H3K14ac benchmarking accessible chromatin. By applying multi-dimensional mass spectrometry, we demonstrated that EXOSC4 interacts with H3K9me3 + acetyls and affects post-transcriptional regulation. Specifically, EXOSC4 depletion leads to down-regulation of the RNA surveillance machinery and increased expression of non-coding transcripts, including anti-sense RNAs. Together, we elucidate the role of a co-modified histone tail and demonstrate its involvement in the RNA machinery and spurious transcription surveillance.

biochemistry↗