CHD8suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing DOI Creative Commons
Emanuela Kerschbamer,

Michele Arnoldi,

Takshashila Tripathi

et al.

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 50(22), P. 12809 - 12828

Published: Dec. 9, 2022

Disruptive mutations in the chromodomain helicase DNA-binding protein 8 gene (CHD8) have been recurrently associated with autism spectrum disorders (ASDs). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications induced pluripotent stem cell-derived neural progenitors. led significant reduction (47.82%) H3K36me3 peaks at bodies, particularly impacting on transcriptional elongation states. specifically affects highly expressed, CHD8-bound genes and correlates altered alternative splicing patterns 462 implicated 'regulation RNA splicing' 'mRNA catabolic process'. Mass spectrometry analysis uncovered novel interaction between regulator heterogeneous nuclear ribonucleoprotein L (hnRNPL), providing first mechanistic insights explain suppression-derived phenotype, partly implicating SETD2, methyltransferase. In summary, our results point toward broad molecular consequences suppression, entailing deposition/maintenance processing regulation as important regulatory processes ASD.

Language: Английский

Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease DOI
Kamakoti P. Bhat, H. Ümit Kanıskan, Jian Jin

et al.

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(4), P. 265 - 286

Published: Jan. 19, 2021

Language: Английский

Citations

180
The role of histone modifications: from neurodevelopment to neurodiseases DOI Creative Commons
Jisu Park, Kyubin Lee, Kyunghwan Kim

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: July 6, 2022

Abstract Epigenetic regulatory mechanisms, including DNA methylation, histone modification, chromatin remodeling, and microRNA expression, play critical roles in cell differentiation organ development through spatial temporal gene regulation. Neurogenesis is a sophisticated complex process by which neural stem cells differentiate into specialized brain types at specific times regions of the brain. A growing body evidence suggests that epigenetic such as modifications, allow fine-tuning coordination spatiotemporal expressions during neurogenesis. Aberrant modifications contribute to neurodegenerative neuropsychiatric diseases. Herein, recent progress understanding regulating embryonic adult neurogenesis comprehensively reviewed. The implicated diseases are also covered, future directions this area provided.

Language: Английский

Citations

165
Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization DOI
Dingfeng Li, Xinyi Gao, Xiaolin Ma

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(5), P. 1059 - 1075.e9

Published: March 7, 2024

Language: Английский

Citations

29
Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder DOI Open Access
Sang Hoon Yoon, Joonhyuk Choi, Won Yong Lee

et al.

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 9(4), P. 966 - 966

Published: March 31, 2020

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental characterized by difficulties in social interaction, language development delays, repeated body movements, and markedly deteriorated activities interests. Environmental factors, such as viral infection, parental age, zinc deficiency, can be plausible contributors to ASD susceptibility. As highly heritable, genetic risk factors involved neurodevelopment, neural communication, interaction provide important clues explaining the etiology of ASD. Accumulated evidence also shows an role epigenetic DNA methylation, histone modification, noncoding RNA, etiology. In this review, we compiled research published date described epidemiology together with environmental underlying different phenotypes

Language: Английский

Citations

127
SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy DOI Creative Commons
Zhentian Wang, Simone Hausmann, Ruitu Lyu

et al.

Cancer Cell, Journal Year: 2020, Volume and Issue: 37(6), P. 834 - 849.e13

Published: May 21, 2020

Language: Английский

Citations

77
Chromatin-mediated alternative splicing regulates cocaine-reward behavior DOI

Song-Jun Xu,

Sonia I. Lombroso, Delaney K. Fischer

et al.

Neuron, Journal Year: 2021, Volume and Issue: 109(18), P. 2943 - 2966.e8

Published: Sept. 1, 2021

Language: Английский

Citations

60
Transcriptional linkage analysis with in vivo AAV-Perturb-seq DOI Creative Commons
António J. Santinha, Esther Klingler,

Maria Kuhn

et al.

Nature, Journal Year: 2023, Volume and Issue: 622(7982), P. 367 - 375

Published: Sept. 20, 2023

The ever-growing compendium of genetic variants associated with human pathologies demands new methods to study genotype-phenotype relationships in complex tissues a high-throughput manner1,2. Here we introduce adeno-associated virus (AAV)-mediated direct vivo single-cell CRISPR screening, termed AAV-Perturb-seq, tuneable and broadly applicable method for transcriptional linkage analysis as well high-resolution phenotyping perturbations vivo. We applied AAV-Perturb-seq using gene editing inhibition systematically dissect the phenotypic landscape underlying 22q11.2 deletion syndrome3,4 genes adult mouse brain prefrontal cortex. identified three 22q11.2-linked involved known previously undescribed pathways orchestrating neuronal functions that explain approximately 40% changes observed 22q11.2-deletion model. Our findings suggest syndrome phenotype found mature neurons may part be due broad dysregulation class disease susceptibility are important dysfunctional RNA processing synaptic function. establishes flexible scalable facilitate causal understanding biological mechanisms potential applications identify interventions therapeutic targets treating disease.

Language: Английский

Citations

43
Role of histone modifications in neurogenesis and neurodegenerative disease development DOI
Anqi Zhao,

Wenhong Xu,

Rui Han

et al.

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 98, P. 102324 - 102324

Published: May 16, 2024

Language: Английский

Citations

16
A MYT1L syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation DOI Creative Commons
Jiayang Chen,

Mary E. Lambo,

Xia Ge

et al.

Neuron, Journal Year: 2021, Volume and Issue: 109(23), P. 3775 - 3792.e14

Published: Oct. 5, 2021

Language: Английский

Citations

57
DNMT3A Haploinsufficiency Results in Behavioral Deficits and Global Epigenomic Dysregulation Shared across Neurodevelopmental Disorders DOI Creative Commons

Diana L. Christian,

Dennis Y. Wu,

Jenna R. Martin

et al.

Cell Reports, Journal Year: 2020, Volume and Issue: 33(8), P. 108416 - 108416

Published: Nov. 1, 2020

Mutations in DNA methyltransferase 3A (DNMT3A) have been detected autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here, we define the effects of DNMT3A associated with neurodevelopmental disease. We show that diverse affect different aspects protein activity lead to shared deficiencies neuronal methylation. Heterozygous knockout mice mimicking disruption disease display growth behavioral alterations consistent human phenotypes. Strikingly, mice, detect global neuron-enriched non-CG methylation, a binding site for Rett syndrome MeCP2. Loss this methylation leads enhancer gene dysregulation overlaps models autism. These findings haploinsufficiency brain uncover pathway as convergence point across disorders.

Language: Английский

Citations

52