Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders DOI Creative Commons
Benjamin H. Weekley,

Newaz I. Ahmed,

Ian Maze

et al.

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 112092 - 112092

Published: Feb. 22, 2025

The evolving field of neuroepigenetics provides important insights into the molecular foundations brain function. Novel sequencing technologies have identified patient-specific mutations and gene expression profiles involved in shaping epigenetic landscape during neurodevelopment disease. Traditional methods to investigate consequences chromatin-related provide valuable phenotypic but often lack information on biochemical mechanisms underlying these processes. Recent studies, however, are beginning elucidate how structural and/or functional aspects histone, DNA, RNA post-translational modifications affect transcriptional landscapes neurological phenotypes. Here, we review identification regulators from genomic studies disease, as well mechanistic findings that reveal intricacies neuronal chromatin regulation. We then discuss serve a guideline for future investigations. end by proposing roadmap therapies exploit coupling them recent advances targeted therapeutics.

Language: Английский

Single-Cell Sequencing of Brain Cell Transcriptomes and Epigenomes DOI Creative Commons
Ethan J. Armand, Junhao Li, Fangming Xie

et al.

Neuron, Journal Year: 2021, Volume and Issue: 109(1), P. 11 - 26

Published: Jan. 1, 2021

Language: Английский

Citations

191
Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice DOI Creative Commons
Mario de la Fuente Revenga, Bohan Zhu, Christopher A. Guevara

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 37(3), P. 109836 - 109836

Published: Oct. 1, 2021

In brief de la Fuente Revenga et al. characterize in-depth molecular changes and behavioral adaptations following exposure to the psychedelic drug DOI.Their findings provide a framework understand lingering effects of psychedelics in synaptic plasticity rodent models depression.

Language: Английский

Citations

154
Multi-omic profiling of the developing human cerebral cortex at the single-cell level DOI Creative Commons
Kaiyi Zhu, Jaroslav Bendl, Samir Rahman

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(41)

Published: Oct. 12, 2023

The cellular complexity of the human brain is established via dynamic changes in gene expression throughout development that mediated, part, by spatiotemporal activity cis-regulatory elements (CREs). We simultaneously profiled and chromatin accessibility 45,549 cortical nuclei across six broad developmental time points from fetus to adult. identified cell type-specific domains which highly correlated with expression. Differentiation pseudotime trajectory analysis indicates at CREs precedes transcription structure play a critical role neuronal lineage commitment. In addition, we mapped temporally specific genetic loci implicated neuropsychiatric traits, including schizophrenia bipolar disorder. Together, our results describe complex regulation composition stages determination shed light on impact alterations disease.

Language: Английский

Citations

58
Developmental and evolutionary dynamics of cis-regulatory elements in mouse cerebellar cells DOI
Ioannis Sarropoulos, Mari Sepp, Robert Frömel

et al.

Science, Journal Year: 2021, Volume and Issue: 373(6558)

Published: July 29, 2021

The cerebellum reveals its genetic programs Gene-regulatory networks govern the development of organs. Sarropoulos et al . analyzed mouse cerebellar in context gene-regulatory networks. Single nuclear profiles analyzing chromatin accessibility about 90,000 cells revealed diversity progenitor and guiding cellular differentiation. footsteps evolution were apparent varying constraints on different cell types. —PJH

Language: Английский

Citations

66
Programmable eukaryotic protein synthesis with RNA sensors by harnessing ADAR DOI
Kaiyi Jiang, Jeremy Koob, Xi Chen

et al.

Nature Biotechnology, Journal Year: 2022, Volume and Issue: 41(5), P. 698 - 707

Published: Oct. 27, 2022

Language: Английский

Citations

66
CTCF regulates global chromatin accessibility and transcription during rod photoreceptor development DOI Creative Commons
Dahong Chen,

Saumya Keremane,

Silu Wang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(9)

Published: Feb. 24, 2025

Chromatin architecture facilitates accurate transcription at a number of loci, but it remains unclear how much chromatin is involved in global transcriptional regulation. Previous work has shown that rapid depletion the architectural protein CTCF cell culture alters organization results surprisingly limited gene expression changes. This discrepancy also been observed when other proteins are depleted, and one possible explanation full changes masked by cellular heterogeneity. We tested this idea performing multiomics analyses with sorted juvenile postmitotic mouse rods, which undergo synchronized development, we identified CTCF-dependent regulation accessibility expression. leads to dysregulation ~20% entire transcriptome (>3,000 genes) ~41% genome (>27,000 sites) before any prominent or physiological phenotypes arise. Importantly, these highly enriched for occupancy euchromatin, suggesting direct binding active loci. mainly promotes frequently inhibits targets, motifs repressors. These findings provide different sometimes opposite conclusions from previous studies, emphasizing need consider heterogeneity cell-type specificity analyses. knockout rods complete degeneration adulthood, indicating an essential role their viability. conclude binds regulates during rod development.

Language: Английский

Citations

1
Interpreting the impact of noncoding structural variation in neurodevelopmental disorders DOI Creative Commons
Eva D’haene, Sarah Vergult

Genetics in Medicine, Journal Year: 2020, Volume and Issue: 23(1), P. 34 - 46

Published: Sept. 25, 2020

The emergence of novel sequencing technologies has greatly improved the identification structural variation, revealing that a human genome harbors tens thousands variants (SVs). Since these SVs primarily impact noncoding DNA sequences, next challenge is one interpretation, not least to improve our understanding disease etiology. However, this task severely complicated by intricacy gene regulatory landscapes embedded within regions, their incomplete annotation, as well dependence on three-dimensional (3D) conformation genome. Also in context neurodevelopmental disorders (NDDs), reports putatively causal, are accumulating and transcriptional regulation presenting itself step toward genetic diagnosis.

Language: Английский

Citations

53
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

51
Spatial Organization of Chromatin: Emergence of Chromatin Structure During Development DOI
Rajarshi P. Ghosh, Barbara J Meyer

Annual Review of Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 37(1), P. 199 - 232

Published: July 6, 2021

Nuclei are central hubs for information processing in eukaryotic cells. The need to fit large genomes into small nuclei imposes severe restrictions on genome organization and the mechanisms that drive genome-wide regulatory processes. How a disordered polymer such as chromatin, which has vast heterogeneity its DNA histone modification profiles, folds discernibly consistent patterns is fundamental question biology. Outstanding questions include how spatially temporally organized regulate cellular processes with high precision whether causally linked transcription regulation. advent of next-generation sequencing, super-resolution imaging, multiplexed fluorescent situ hybridization, single-molecule imaging individual living cells caused resurgence efforts understand spatiotemporal genome. In this review, we discuss structural mechanistic properties at different length scales examine changes higher-order chromatin during important developmental transitions.

Language: Английский

Citations

49
NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons DOI Creative Commons
Nicole Hamagami, Dennis Y. Wu,

Adam W. Clemens

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(9), P. 1412 - 1428.e7

Published: April 24, 2023

Language: Английский

Citations

23