Cargando…

Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain

Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brain’s 3D spatial organization is essential for building a complete molecula...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Hanqing, Zeng, Qiurui, Zhou, Jingtian, Bartlett, Anna, Wang, Bang-An, Berube, Peter, Tian, Wei, Kenworthy, Mia, Altshul, Jordan, Nery, Joseph R., Chen, Huaming, Castanon, Rosa G., Zu, Songpeng, Li, Yang Eric, Lucero, Jacinta, Osteen, Julia K., Pinto-Duarte, Antonio, Lee, Jasper, Rink, Jon, Cho, Silvia, Emerson, Nora, Nunn, Michael, O’Connor, Carolyn, Yao, Zizhen, Smith, Kimberly A., Tasic, Bosiljka, Zeng, Hongkui, Luo, Chongyuan, Dixon, Jesse R., Ren, Bing, Behrens, M. Margarita, Ecker, Joseph R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153407/
https://www.ncbi.nlm.nih.gov/pubmed/37131654
http://dx.doi.org/10.1101/2023.04.16.536509
_version_ 1785035924509294592
author Liu, Hanqing
Zeng, Qiurui
Zhou, Jingtian
Bartlett, Anna
Wang, Bang-An
Berube, Peter
Tian, Wei
Kenworthy, Mia
Altshul, Jordan
Nery, Joseph R.
Chen, Huaming
Castanon, Rosa G.
Zu, Songpeng
Li, Yang Eric
Lucero, Jacinta
Osteen, Julia K.
Pinto-Duarte, Antonio
Lee, Jasper
Rink, Jon
Cho, Silvia
Emerson, Nora
Nunn, Michael
O’Connor, Carolyn
Yao, Zizhen
Smith, Kimberly A.
Tasic, Bosiljka
Zeng, Hongkui
Luo, Chongyuan
Dixon, Jesse R.
Ren, Bing
Behrens, M. Margarita
Ecker, Joseph R
author_facet Liu, Hanqing
Zeng, Qiurui
Zhou, Jingtian
Bartlett, Anna
Wang, Bang-An
Berube, Peter
Tian, Wei
Kenworthy, Mia
Altshul, Jordan
Nery, Joseph R.
Chen, Huaming
Castanon, Rosa G.
Zu, Songpeng
Li, Yang Eric
Lucero, Jacinta
Osteen, Julia K.
Pinto-Duarte, Antonio
Lee, Jasper
Rink, Jon
Cho, Silvia
Emerson, Nora
Nunn, Michael
O’Connor, Carolyn
Yao, Zizhen
Smith, Kimberly A.
Tasic, Bosiljka
Zeng, Hongkui
Luo, Chongyuan
Dixon, Jesse R.
Ren, Bing
Behrens, M. Margarita
Ecker, Joseph R
author_sort Liu, Hanqing
collection PubMed
description Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brain’s 3D spatial organization is essential for building a complete molecular atlas of brain cell types and understanding their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) and multi-omic (snm3C-seq(1)) sequencing technologies to generate 301,626 methylomes and 176,003 chromatin conformation/methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell type taxonomy that contains 4,673 cell groups and 261 cross-modality-annotated subclasses. We identified millions of differentially methylated regions (DMRs) across the genome, representing potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide multiplexed error-robust fluorescence in situ hybridization (MERFISH(2)) data validated the association of this spatial epigenetic diversity with transcription and allowed the mapping of the DNA methylation and topology information into anatomical structures more precisely than our dissections. Furthermore, multi-scale chromatin conformation diversities occur in important neuronal genes, highly associated with DNA methylation and transcription changes. Brain-wide cell type comparison allowed us to build a regulatory model for each gene, linking transcription factors, DMRs, chromatin contacts, and downstream genes to establish regulatory networks. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a companion whole-brain SMART-seq(3) dataset. Our study establishes the first brain-wide, single-cell resolution DNA methylome and 3D multi-omic atlas, providing an unparalleled resource for comprehending the mouse brain’s cellular-spatial and regulatory genome diversity.
format Online
Article
Text
id pubmed-10153407
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Cold Spring Harbor Laboratory
record_format MEDLINE/PubMed
spelling pubmed-101534072023-05-03 Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain Liu, Hanqing Zeng, Qiurui Zhou, Jingtian Bartlett, Anna Wang, Bang-An Berube, Peter Tian, Wei Kenworthy, Mia Altshul, Jordan Nery, Joseph R. Chen, Huaming Castanon, Rosa G. Zu, Songpeng Li, Yang Eric Lucero, Jacinta Osteen, Julia K. Pinto-Duarte, Antonio Lee, Jasper Rink, Jon Cho, Silvia Emerson, Nora Nunn, Michael O’Connor, Carolyn Yao, Zizhen Smith, Kimberly A. Tasic, Bosiljka Zeng, Hongkui Luo, Chongyuan Dixon, Jesse R. Ren, Bing Behrens, M. Margarita Ecker, Joseph R bioRxiv Article Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brain’s 3D spatial organization is essential for building a complete molecular atlas of brain cell types and understanding their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) and multi-omic (snm3C-seq(1)) sequencing technologies to generate 301,626 methylomes and 176,003 chromatin conformation/methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell type taxonomy that contains 4,673 cell groups and 261 cross-modality-annotated subclasses. We identified millions of differentially methylated regions (DMRs) across the genome, representing potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide multiplexed error-robust fluorescence in situ hybridization (MERFISH(2)) data validated the association of this spatial epigenetic diversity with transcription and allowed the mapping of the DNA methylation and topology information into anatomical structures more precisely than our dissections. Furthermore, multi-scale chromatin conformation diversities occur in important neuronal genes, highly associated with DNA methylation and transcription changes. Brain-wide cell type comparison allowed us to build a regulatory model for each gene, linking transcription factors, DMRs, chromatin contacts, and downstream genes to establish regulatory networks. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a companion whole-brain SMART-seq(3) dataset. Our study establishes the first brain-wide, single-cell resolution DNA methylome and 3D multi-omic atlas, providing an unparalleled resource for comprehending the mouse brain’s cellular-spatial and regulatory genome diversity. Cold Spring Harbor Laboratory 2023-04-18 /pmc/articles/PMC10153407/ /pubmed/37131654 http://dx.doi.org/10.1101/2023.04.16.536509 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Liu, Hanqing
Zeng, Qiurui
Zhou, Jingtian
Bartlett, Anna
Wang, Bang-An
Berube, Peter
Tian, Wei
Kenworthy, Mia
Altshul, Jordan
Nery, Joseph R.
Chen, Huaming
Castanon, Rosa G.
Zu, Songpeng
Li, Yang Eric
Lucero, Jacinta
Osteen, Julia K.
Pinto-Duarte, Antonio
Lee, Jasper
Rink, Jon
Cho, Silvia
Emerson, Nora
Nunn, Michael
O’Connor, Carolyn
Yao, Zizhen
Smith, Kimberly A.
Tasic, Bosiljka
Zeng, Hongkui
Luo, Chongyuan
Dixon, Jesse R.
Ren, Bing
Behrens, M. Margarita
Ecker, Joseph R
Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain
title Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain
title_full Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain
title_fullStr Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain
title_full_unstemmed Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain
title_short Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain
title_sort single-cell dna methylome and 3d multi-omic atlas of the adult mouse brain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153407/
https://www.ncbi.nlm.nih.gov/pubmed/37131654
http://dx.doi.org/10.1101/2023.04.16.536509
work_keys_str_mv AT liuhanqing singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT zengqiurui singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT zhoujingtian singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT bartlettanna singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT wangbangan singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT berubepeter singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT tianwei singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT kenworthymia singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT altshuljordan singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT neryjosephr singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT chenhuaming singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT castanonrosag singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT zusongpeng singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT liyangeric singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT lucerojacinta singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT osteenjuliak singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT pintoduarteantonio singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT leejasper singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT rinkjon singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT chosilvia singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT emersonnora singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT nunnmichael singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT oconnorcarolyn singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT yaozizhen singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT smithkimberlya singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT tasicbosiljka singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT zenghongkui singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT luochongyuan singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT dixonjesser singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT renbing singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT behrensmmargarita singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain
AT eckerjosephr singlecelldnamethylomeand3dmultiomicatlasoftheadultmousebrain