Cell-type-specific 3D-genome organization and transcription regulation in the brain DOI Creative Commons

Shiwei Liu,

Pu Zheng, Cosmos Yuqi Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 5, 2023

Abstract 3D organization of the genome plays a critical role in regulating gene expression. However, it remains unclear how chromatin differs among different cell types brain. Here we used genome-scale DNA and RNA imaging to investigate 3D-genome transcriptionally distinct primary motor cortex mouse We uncovered wide spectrum differences nuclear architecture types, ranging from physical size nucleus active-inactive compartmentalization radial positioning loci within nucleus. These cell-type-dependent variations exhibited strong correlation with both total transcriptional activity regulation cell-type-specific marker genes. Moreover, found that methylated-DNA-binding protein MeCP2 regulates transcription divergent manner, depending on positions loci, through modulating compartmentalization.

Language: Английский

Single-cell DNA methylome and 3D multi-omic atlas of the adult mouse brain DOI Creative Commons
Hanqing Liu, Qiurui Zeng, Jingtian Zhou

et al.

Nature, Journal Year: 2023, Volume and Issue: 624(7991), P. 366 - 377

Published: Dec. 13, 2023

Cytosine DNA methylation is essential in brain development and implicated various neurological disorders. Understanding diversity across the entire a spatial context fundamental for complete molecular atlas of cell types their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) multi-omic (snm3C-seq)

Language: Английский

Citations

56
Single-cell multiplex chromatin and RNA interactions in ageing human brain DOI Creative Commons
Xingzhao Wen, Zhifei Luo,

Wenxin Zhao

et al.

Nature, Journal Year: 2024, Volume and Issue: 628(8008), P. 648 - 656

Published: March 27, 2024

Abstract Dynamically organized chromatin complexes often involve multiplex interactions and sometimes chromatin-associated RNA 1–3 . Chromatin complex compositions change during cellular differentiation ageing, are expected to be highly heterogeneous among terminally differentiated single cells 4–7 Here we introduce the multinucleic acid interaction mapping in (MUSIC) technique for concurrent profiling of interactions, gene expression RNA–chromatin associations within individual nuclei. When applied 14 human frontal cortex samples from older donors, MUSIC delineated diverse cortical cell types states. We observed that nuclei exhibiting fewer short-range were correlated with both an ‘older’ transcriptomic signature Alzheimer’s disease pathology. Furthermore, type contacts between cis quantitative trait loci a promoter tends which these specifically affect their target gene. In addition, female exhibit XIST non-coding chromosome X, along spatial organizations X chromosomes. presents potent tool exploration architecture transcription at resolution tissues.

Language: Английский

Citations

24
Cell type–specific 3D-genome organization and transcription regulation in the brain DOI Creative Commons

Shiwei Liu,

Cosmos Yuqi Wang, Pu Zheng

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(9)

Published: Feb. 26, 2025

3D organization of the genome plays a critical role in regulating gene expression. How 3D-genome differs among different cell types and relates to type–dependent transcriptional regulation remains unclear. Here, we used genome-scale DNA RNA imaging investigate transcriptionally distinct mouse cerebral cortex. We uncovered wide spectrum differences nuclear architecture types, ranging from size nucleus higher-order chromosome structures radial positioning chromatin loci within nucleus. These variations exhibit strong correlations with both total activity type–specific marker genes. Moreover, found that methylated binding protein MeCP2 promotes active-inactive segregation regulates transcription position–dependent manner is highly correlated its function modulating compartmentalization.

Language: Английский

Citations

2
Schizophrenia genomics: genetic complexity and functional insights DOI
Patrick F. Sullivan, Shuyang Yao, Jens Hjerling‐Leffler

et al.

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(9), P. 611 - 624

Published: July 19, 2024

Language: Английский

Citations

15
Chromosome structure in Drosophila is determined by boundary pairing not loop extrusion DOI Creative Commons
Xinyang Bing, Wenfan Ke, Miki Fujioka

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Feb. 5, 2024

Two different models have been proposed to explain how the endpoints of chromatin looped domains (‘TADs’) in eukaryotic chromosomes are determined. In first, a cohesin complex extrudes loop until it encounters boundary element roadblock, generating stem-loop. this model, boundaries functionally autonomous: they an intrinsic ability halt movement incoming complexes that is independent properties neighboring boundaries. second, loops generated by boundary:boundary pairing. non-autonomous, and their form depends upon well match with neighbors. Moreover, unlike loop-extrusion pairing interactions can generate both stem-loops circle-loops. We used combination MicroC analyze TADs organized, experimental manipulations even skipped TAD boundary, homie , test predictions ‘loop-extrusion’ ‘boundary-pairing’ models. Our findings incompatible instead suggest flies determined mechanism which elements physically pair partners, either head-to-head or head-to-tail, varying degrees specificity. Although our experiments do not address partners find each other, unlikely require extrusion.

Language: Английский

Citations

9
How the gut microbiota impacts neurodegenerative diseases by modulating CNS immune cells DOI Creative Commons
Philipp Schaible,

Julia Henschel,

Daniel Erny

et al.

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: March 3, 2025

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative worldwide. Amyloid-β (Aβ) accumulation and neurofibrillary tangles are two key histological features resulting in progressive irreversible neuronal loss cognitive decline. The macrophages of central nervous system (CNS) belong to innate immune comprise parenchymal microglia CNS-associated (CAMs) at CNS interfaces (leptomeninges, perivascular space choroid plexus). Microglia CAMs have received attention as they may play a role onset progression e. g., by clearing amyloid beta through phagocytosis. Genome-wide association studies (GWAS) revealed that human express numerous risk genes for AD, further highlighting their potentially critical AD pathogenesis. tightly controlled environmental factors, such host microbiota. Notably, it was reported composition gut microbiota differed between patients healthy individuals. Hence, emerging analyzed impact bacteria different preclinical mouse models well clinical studies, enabling promising new therapeutic options.

Language: Английский

Citations

1
Temporally distinct 3D multi-omic dynamics in the developing human brain DOI Creative Commons

Matthew G. Heffel,

Jingtian Zhou, Yi Zhang

et al.

Nature, Journal Year: 2024, Volume and Issue: 635(8038), P. 481 - 489

Published: Oct. 9, 2024

The human hippocampus and prefrontal cortex play critical roles in learning cognition

Language: Английский

Citations

8
Three-dimensional chromatin reorganization regulates B cell development during ageing DOI Creative Commons
Fei Ma, Yaqiang Cao,

Hansen Du

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(6), P. 991 - 1002

Published: June 1, 2024

The contribution of three-dimensional genome organization to physiological ageing is not well known. Here we show that large-scale chromatin reorganization distinguishes young and old bone marrow progenitor (pro-) B cells. These changes result in increased interactions at the compartment level reduced within topologically associated domains (TADs). gene encoding Ebf1, a key cell regulator, switches from A with age. Genetically reducing Ebf1 recapitulates some features pro-B TADs are most age contain genes important for development, including immunoglobulin heavy chain (Igh) locus. Weaker intra-TAD Igh correlate altered variable (V), diversity (D) joining (J) recombination. Our observations implicate as major driver phenotypes impair lymphopoiesis

Language: Английский

Citations

7
Gene-environmental regulation of the postnatal post-mitotic neuronal maturation DOI Creative Commons

Gabrielle S. Prince,

Molly Reynolds,

Verdion Martina

et al.

Trends in Genetics, Journal Year: 2024, Volume and Issue: 40(6), P. 480 - 494

Published: April 23, 2024

Embryonic neurodevelopment, particularly neural progenitor differentiation into post-mitotic neurons, has been extensively studied. While the number and composition of neurons remain relatively constant from birth to adulthood, brain undergoes significant postnatal maturation marked by major property changes frequently disrupted in diseases. This review first summarizes recent characterizations functional molecular nervous system. We then regulatory mechanisms controlling precise gene expression crucial for intricate sequence events, highlighting experience-dependent versus cell-intrinsic genetic timer mechanisms. Despite advances understanding gene-environmental regulation neuronal maturation, many aspects unknown. The concludes with our perspective on exciting future research directions next decade.

Language: Английский

Citations

5
Expansion in situ genome sequencing links nuclear abnormalities to hotspots of aberrant euchromatin repression DOI
Ajay Labade, Zachary Chiang,

Caroline Comenho

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 26, 2024

Microscopy and genomics are both used to characterize cell function, but approaches connect the two types of information lacking, particularly at subnuclear resolution. While emerging multiplexed imaging methods can simultaneously localize genomic regions nuclear proteins, their ability accurately measure DNA-protein interactions is constrained by diffraction limit optical microscopy. Here, we describe expansion in situ genome sequencing (ExIGS), a technology that enables DNA superresolution localization proteins single cells. We applied ExIGS fibroblast cells derived from an individual with Hutchinson-Gilford progeria syndrome how variation morphology affects spatial chromatin organization. Using this data, discovered lamin abnormalities linked hotspots aberrant euchromatin repression may erode identity. Further, show heterogeneously increase repressive environment nucleus tissues aged These results demonstrate serve as generalizable platform for connecting changes gene regulation across disease contexts.

Language: Английский

Citations

5