Abstract:Summary
The serine/arginine-rich (SR) family of splicing factors plays important roles in mRNA splicing activation, repression, export, stabilization, and translation. SR-splicing factor 5 (SRSF5) is a glucose-inducible protein that promotes tumor cell growth. However, the functional role of SRSF5 in tissue development and disease remains unknown. Here,
Srsf5
knockout (
Srsf5
−/−
) mice were generated using CRISPR-Cas9. Mutant mice were … Show more
“…Examination of publicly available data identified several molecular partners of HP1γ that when inactivated, result in a significant increase in the splicing noise. These partners include PPL1 28 , a peptidyl prolyl isomerase-like spliceosome component, ZC3H13, a zinc finger protein recruiting RNA methyl transferases involved in N 6-adenosine methylation (m6A) modification 29 , 30 , and the Ser/Arg-rich protein SRSF5 31 (Supplementary Fig. 11 ).…”
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.
“…Examination of publicly available data identified several molecular partners of HP1γ that when inactivated, result in a significant increase in the splicing noise. These partners include PPL1 28 , a peptidyl prolyl isomerase-like spliceosome component, ZC3H13, a zinc finger protein recruiting RNA methyl transferases involved in N 6-adenosine methylation (m6A) modification 29 , 30 , and the Ser/Arg-rich protein SRSF5 31 (Supplementary Fig. 11 ).…”
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.
“…Essential roles of SR proteins have been reported for sex determination [ 40 , 41 ], cell differentiation [ 42 , 43 ], development of the brain [ 44 , 45 ] and heart [ 10 , 46 , 47 ], the immune system [ 48 , 49 ], and many types of cancer [ 12 , 50 , 51 ]. Here, we focus on the known functional mechanisms of SR proteins, and discuss the importance of these functions in various cancers.…”
Section: Functional Mechanisms Of Sr Proteins In Cancermentioning
Alternative splicing of pre-mRNAs is a fundamental step in RNA processing required for gene expression in most metazoans. Serine and arginine-rich proteins (SR proteins) comprise a family of multifunctional proteins that contain an RNA recognition motif (RRM) and the ultra-conserved arginine/serine-rich (RS) domain, and play an important role in precise alternative splicing. Increasing research supports SR proteins as also functioning in other RNA-processing-related mechanisms, such as polyadenylation, degradation, and translation. In addition, SR proteins interact with N6-methyladenosine (m6A) regulators to modulate the methylation of ncRNA and mRNA. Dysregulation of SR proteins causes the disruption of cell differentiation and contributes to cancer progression. Here, we review the distinct biological characteristics of SR proteins and their known functional mechanisms during carcinogenesis. We also summarize the current inhibitors that directly target SR proteins and could ultimately turn SR proteins into actionable therapeutic targets in cancer therapy.
“… 21 HnRNP A1 + /− mice exhibited disrupted blood pressure and heart rates. 22 Animal models have demonstrated that the absence of SRSF1, 23 SRSF5, 24 SRSF10, 25 hnRNP U 26 or hnRNP L 27 , 28 phenocopy human cardiovascular diseases such as atrial septal defects, heart failure, noncompaction of the ventricular myocardium and diabetic heart. Fig.…”
Section: Splicing Factors and Cardiovascular Diseasementioning
confidence: 99%
“… Splicing factors Example of genes regulated by splicing factors through AS Study source Related cardiac phenotypes Related cardiac diseases References SF3B1 Khk-C Mice Diastolic dysfunction Cardiac hypertrophy 44 SRSF1 Camk2d Mice Cardiac remodelling and fibrosis; fuzzy Z-lines and shortened sarcomeres; hypercontraction; disrupted calcium handling. DCM 23 SRSF3 mTOR Mice Systolic dysfunction; Heart failure 21 SRSF5 Myomesin Mice Noncompaction of the ventricular myocardium; increased left ventricular internal diameter and volume; irregular electrocardiogram cardiomyopathy with noncompaction of the ventricular myocardium 24 SRSF10 Triadin Mice Atrial septal defects; ventricular septal defects; thinner myocardium; atrioventricular canal defect; disrupted calcium handling 25 HnRNP A1 Mef2c, Lrrfip1, Usp28 and Abcc9 Mice Increased systolic pressures; increased heart rates; increased RR interval, PR interval and P duration DCM 22 HnRNP U Titin and Camk2d Mice Aberrant cardiomyocyte arrangement; dramatic increase of left ventricular anterior-to-posterior wall diameter; decreased fractional shortening; abnormal calcium handling activities. Heart failure 26 HnRNP L CLIP1, MED23, Tmem184b , and CaV1.2 Mice; humans; rats Reduced sensitivity of CaV1.2 channels to nifedipine.…”
Section: Splicing Factors and Cardiovascular Diseasementioning
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