Alternative splicing links histone modifications to stem cell fate decision

Abstract

Understanding embryonic stem cell (ESC) fate decision between self-renewal and proper differentiation is important for developmental biology and regenerative medicine. Attentions have focused on underlying mechanisms involving histone modifications (HMs), alternative pre-mRNA splicing (AS), and cell-cycle progression. However, their intricate interrelations and joint contributions to ESC fate decision remain unclear. We performed integrative analyses on transcriptomic and epigenomic data derived from human ESC (hESC) and five types of differentiated cells. We identified thousands of AS exons and revealed their development-and lineage-dependent characterizations. Following the observation that dynamic HM changes predominantly occur in AS exons upon hESCs differentiation, we identified 3 of 16 investigated HMs (H3K36me3, H3K27ac, and H4K8ac) that are strongly associated with 52.8% of hESC differentiation-related AS events. Further analyses showed that the HM-associated AS genes predominantly function in G2/M phases and ATM/ATR-mediated DNA damage response pathway for cell differentiation, whereas HM-unassociated AS genes enrich in G1 phase and pathways for self-renewal. These results imply a potential epigenetic mechanism by which some HMs contribute to ESC fate decision through the AS regulation of specific pathways and cell-cycle genes. We exemplified the potential mechanism by a cell cycle-related transcription factor, PBX1, which regulates the pluripotency regulatory network by binding to NANOG. We found that the isoform switch between PBX1a and PBX1b is strongly associated with H3K36me3 alteration and implicated in hESC fate determination. Supported by extended dataset from Roadmap/ENCODE projects, we identified the alternative splicing of PBX1 as a novel candidate linking H3K36me3 to embryonic stem cell fate decision.

Identification of Candidate Biomarkers for Salt Sensitivity of Blood Pressure by Integrated Bioinformatics Analysis

“…SRSF5 (serine-and arginine-rich splicing factor 5), SRSF1 (serine-and arginine-rich splicing factor 1), PNN (pinin, desmosome-associated protein), and PNISR (PNN-interacting serine-and arginine-rich protein) were considered to have marked effects on the regulation of the RNA AS process (Bush et al, 2017;Latorre and Harries, 2017). AS is a mechanism by which a single gene can generate multiple different transcripts and subsequently produce various proteins (Xu et al, 2018). A large number of studies on the association of RNA AS and hypertension have been reported, however, little attention has been focused on the correlation between AS and SSBP (Hu et al, 2017;Dlamini et al, 2019).…”

BBSdb, an open resource for bacterial biofilm-associated proteins

“…In this study, we employed the RF, SVM, KNN, XGBoost and LR algorithms to build models and make predictions. According to the result, RF, which has been widely used in bioinformatics and computational biology 15,16 , had stronger power than other four classifiers.…”

Histone methyltransferase SETD2: a potential tumor suppressor in solid cancers

“…Recently, SETD2 protein has been identified to interact with STAT1 (signal transducers and activators of transcription), finally causing dysfunction of cell signaling pathway [43]. Besides, SETD2 and H3K36me3 are implicated in alternative splicing (AS) [44,45], and this event is related to histone modification [46][47][48][49]. H3K36me3 is also related to crosstalk [11] and genomic integrity (Figure 1) [33]. )…”