HP1γ binding pre‐mRNA intronic repeats modulates RNA splicing decisions

Rachez, Christophe; Legendre, Rachel; Varet, Hugo; Yi, Jia; Kornobis, Étienne; Muchardt, Christian

doi:10.15252/embr.202052320

Cited by 14 publications

(9 citation statements)

References 61 publications

(87 reference statements)

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“…They play key roles in formation and maintenance of heterochromatin, thereby participating in transcriptional gene silencing 3 . In parallel, HP1 proteins display RNA binding activity, as described in multiple species 4 , and in mammals, in vitro studies have shown that HP1γ binds intronic repetitive motifs of pre-messenger RNA 5 to promote co-transcriptional pre-mRNA processing and alternative splicing 6 – 8 . Here, we show that, in the gut epithelium, HP1γ-mediated regulation of both transcription and RNA metabolism is required for gut homeostasis and important in the understanding of IBD.…”

Section: Introductionmentioning

confidence: 93%

The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis

et al. 2022

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Defects in RNA splicing have been linked to human disorders, but remain poorly explored in inflammatory bowel disease (IBD). Here, we report that expression of the chromatin and alternative splicing regulator HP1γ is reduced in ulcerative colitis (UC). Accordingly, HP1γ gene inactivation in the mouse gut epithelium triggers IBD-like traits, including inflammation and dysbiosis. In parallel, we find that its loss of function broadly increases splicing noise, favoring the usage of cryptic splice sites at numerous genes with functions in gut biology. This results in the production of progerin, a toxic splice variant of prelamin A mRNA, responsible for the Hutchinson-Gilford Progeria Syndrome of premature aging. Splicing noise is also extensively detected in UC patients in association with inflammation, with progerin transcripts accumulating in the colon mucosa. We propose that monitoring HP1γ activity and RNA splicing precision can help in the management of IBD and, more generally, of accelerated aging.

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Section: Introductionmentioning

confidence: 93%

The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis

et al. 2022

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“…This difference in binding pattern is difficult to interpret given the differences in genome organization between D. melanogaster and humans: The mean length for introns in the D. melanogaster genome is 86 bp, while it is 1747 bp for the human genome [ 126 , 127 ], and gene lengths and size of intergenic regions differ significantly as well. The binding of HP1γ is hypothesized to control co-transcriptional splicing of pre-mRNA based on a study of mouse cell lines [ 124 ]. Human HP1γ binding and deposition of H3K9me3 favor the inclusion of variant exons at the CD44 gene [ 125 ].…”

Section: Hp1 Proteins From Other Species Also Exhibit Both Activating...mentioning

confidence: 99%

Functions of HP1 proteins in transcriptional regulation

Schoelz

Riddle

2022

Epigenetics & Chromatin

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In eukaryotes, DNA is packaged into chromatin, which presents significant barriers to transcription. Non-histone chromatin proteins such as the Heterochromatin Protein 1 (HP1) proteins are critical regulators of transcription, contributing to gene regulation through a variety of molecular mechanisms. HP1 proteins are highly conserved, and many eukaryotic genomes contain multiple HP1 genes. Given the presence of multiple HP1 family members within a genome, HP1 proteins can have unique as well as shared functions. Here, we review the mechanisms by which HP1 proteins contribute to the regulation of transcription. Focusing on the Drosophila melanogaster HP1 proteins, we examine the role of these proteins in regulating the transcription of genes, transposable elements, and piRNA clusters. In D. melanogaster, as in other species, HP1 proteins can act as transcriptional repressors and activators. The available data reveal that the precise impact of HP1 proteins on gene expression is highly context dependent, on the specific HP1 protein involved, on its protein partners present, and on the specific chromatin context the interaction occurs in. As a group, HP1 proteins utilize a variety of mechanisms to contribute to transcriptional regulation, including both transcriptional (i.e. chromatin-based) and post-transcriptional (i.e. RNA-based) processes. Despite extensive studies of this important protein family, open questions regarding their functions in gene regulation remain, specifically regarding the role of hetero- versus homodimerization and post-translational modifications of HP1 proteins.

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“…In addition to their "caretaker" function in heterochromatin, HP1 proteins display RNA binding activity described across the species 3 . In mammals, in vitro studies have shown that HP1g binds intronic repetitive motifs of pre-messenger RNA 4 and promote cotranscriptional RNA processing as well as alternative splicing [5][6] . These studies suggest a role in RNA metabolism homeostasis that remains unexplored in intestinal disorders, in sharp contrast to neurodegenerative, cardiac or premature aging diseases 7 .…”

Section: Mainmentioning

confidence: 99%

The Heterochromatin protein 1 is a master regulator in RNA splicing precision deficient in ulcerative colitis

Mata-Garrido

Chang-Marchand

Cherbuy

et al. 2020

Preprint

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Altered RNA maturation and decay have well-documented effects on tissue longevity. Yet, RNA metabolism is poorly investigated in the gut epithelium, a constantly renewing tissue particularly challenged by ageing. We found that inactivation of the epigenetic regulator HP1γ in the mouse gut epithelium results in accelerated ageing associated with both ectopic expression of ribosomal RNAs and accumulation of miss-spliced messenger RNAs. A consequence of the latter is the production of progerin, a spliced product of the LMNA gene associated with the Hutchinson Gilford Syndrome. Production of progerin transcript increased naturally in the mouse ageing gut, in correlation with a reduced HP1γ expression. Thus, progerin is a candidate marker of aging of the gut epithelium, while HP1γ inactivation emerges as a new model for accelerated aging in this tissue.

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HP1γ binding pre‐mRNA intronic repeats modulates RNA splicing decisions

Cited by 14 publications

References 61 publications

The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis

The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis

Functions of HP1 proteins in transcriptional regulation

The Heterochromatin protein 1 is a master regulator in RNA splicing precision deficient in ulcerative colitis

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