The Crosstalk Between Epigenetic Mechanisms and Alternative RNA Processing Regulation

Zhang, Jian; Zhang, Yizhe; Jiang, Jing; Duan, Cheng‐Guo

doi:10.3389/fgene.2020.00998

Cited by 51 publications

(48 citation statements)

References 101 publications

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“…Methylation is known to regulate splicing [54][55][56][57], but alternative isoforms of DNA methyltransferases genes or genes regulating chromatin conformation or methylation can also modulate methylation profiles [32]. Although mutations in genes required for splicing and methylation commonly occur in leukemia, and a mutation in a splicing factor (SRSF2) has been shown to impact methylation in acute myeloid leukaemia [58], the interaction of these two processes has not been described in CLL patients carrying SF3B1 mut .…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, all three DNA methyltransferases (DNMTs) are subjected to alternative splicing [29][30][31] and, therefore, mutations in splicing factors can potentially lead to changes in the methylation profiles, either directly by affecting the splicing of the DNA methyltransferases and DNA demethylases genes, or by alternatively spliced isoforms of the chromatin and methylation regulators, such as non-coding RNAs [32]. Thus, to achieve a better understanding on the methylome changes in CLL patients and how they might be connected to mutations in SF3B1, we compared genome-wide methylation profiles of CLL patients with (SF3B1 mut ) and without (SF3B1 WT ) SF3B1 mutations.…”

Section: Introductionmentioning

confidence: 99%

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Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients

Pacholewska

Grimm

Herling

et al. 2021

IJMS

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Mutations in splicing factor genes have a severe impact on the survival of cancer patients. Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated genes in chronic lymphocytic leukemia (CLL); patients carrying these mutations have a poor prognosis. Since the splicing machinery and the epigenome are closely interconnected, we investigated whether these alterations may affect the epigenomes of CLL patients. While an overall hypomethylation during CLL carcinogenesis has been observed, the interplay between the epigenetic stage of the originating B cells and SF3B1 mutations, and the subsequent effect of the mutations on methylation alterations in CLL, have not been investigated. We profiled the genome-wide DNA methylation patterns of 27 CLL patients with and without SF3B1 mutations and identified local decreases in methylation levels in SF3B1mut CLL patients at 67 genomic regions, mostly in proximity to telomeric regions. These differentially methylated regions (DMRs) were enriched in gene bodies of cancer-related signaling genes, e.g., NOTCH1, HTRA3, and BCL9L. In our study, SF3B1 mutations exclusively emerged in two out of three epigenetic stages of the originating B cells. However, not all the DMRs could be associated with the methylation programming of B cells during development, suggesting that mutations in SF3B1 cause additional epigenetic aberrations during carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients

Pacholewska

Grimm

Herling

et al. 2021

IJMS

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“…This association of environment‐induced alternative splicing activity with regulators offers an elegant means of rapidly deploying phenotypic plasticity to a system under stress. It is perhaps not surprising, then, that gene‐associated DNA methylation repatterning occurs within gene networks that align with stress response pathways and phenotype changes (Yang et al ., 2020; Kundariya et al ., 2020); subtle methylation changes may be sufficient to adjust or respond to local splicing changes that relax phenotypic constraints (Zhang et al ., 2020).…”

Section: Alternative Rna Splicing As a Nuclear Response To Organellar Signalingmentioning

confidence: 99%

A new take on organelle‐mediated stress sensing in plants

Dopp

Yang²,

Mackenzie³

2021

New Phytologist

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Summary Plants are able to adjust phenotype in response to changes in the environment. This system depends on an internal capacity to sense environmental conditions and to process this information to plant response. Recent studies have pointed to mitochondria and plastids as important environmental sensors, capable of perceiving stressful conditions and triggering gene expression, epigenomic, metabolic and phytohormone changes in the plant. These processes involve integrated gene networks that ultimately modulate the energy balance between growth and plant defense. This review attempts to link several unusual recent findings into a comprehensive hypothesis for the regulation of plant phenotypic plasticity.

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“…Altogether our results and other published data demonstrate that SLU7 and DNMT1 control gene expression at different levels, but both play essential roles maintaining genome integrity, cell proliferation and cell survival. Recent results have demonstrated a narrow connection and interplay between the different mechanisms implicated in the regulation of gene expression including DNA methylation and alternative splicing ( 20 , 21 ). Having demonstrated that SLU7 regulates both splicing and transcription, we decided to investigate whether SLU7 also regulates DNA methylation, representing a new hub integrating different levels of gene expression regulation.…”

Section: Introductionmentioning

confidence: 99%

The splicing regulator SLU7 is required to preserve DNMT1 protein stability and DNA methylation

Recalde

Gárate-Rascón

Elizalde

et al. 2021

Nucleic Acids Research

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Gene expression is finely and dynamically controlled through the tightly coordinated and interconnected activity of epigenetic modulators, transcription and splicing factors and post-translational modifiers. We have recently identified the splicing factor SLU7 as essential for maintaining liver cell identity and genome integrity and for securing cell division both trough transcriptional and splicing mechanisms. Now we uncover a new function of SLU7 controlling gene expression at the epigenetic level. We show that SLU7 is required to secure DNMT1 protein stability and a correct DNA methylation. We demonstrate that SLU7 is part in the chromatome of the protein complex implicated in DNA methylation maintenance interacting with and controlling the integrity of DNMT1, its adaptor protein UHRF1 and the histone methyl-transferase G9a at the chromatin level. Mechanistically, we found that SLU7 assures DNMT1 stability preventing its acetylation and degradation by facilitating its interaction with HDAC1 and the desubiquitinase USP7. Importantly, we demonstrate that this DNMT1 dependency on SLU7 occurs in a large panel of proliferating cell lines of different origins and in in vivo models of liver proliferation. Overall, our results uncover a novel and non-redundant role of SLU7 in DNA methylation and present SLU7 as a holistic regulator of gene expression.

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The Crosstalk Between Epigenetic Mechanisms and Alternative RNA Processing Regulation

Cited by 51 publications

References 101 publications

Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients

Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients

A new take on organelle‐mediated stress sensing in plants

The splicing regulator SLU7 is required to preserve DNMT1 protein stability and DNA methylation

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