Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex
John K. Mich,Lucas T. Graybuck,Hess Erik,Joseph T. Mahoney,Yoshiko Kojima,Yi Ding,Saroja Somasundaram,Jeremy A. Miller,Natalie Weed,Victoria Omstead,Yemeserach Bishaw,Nadiya V. Shapovalova,Refugio A. Martinez,Olivia Fong,Shenqin Yao,Marty Mortrud,Peter Chong,Luke Loftus,Darren Bertagnolli,Jeff Goldy,Tamara Casper,Nick Dee,Ximena Opitz-Araya,Ali Cetin,Kimberly A. Smith,Ryder P. Gwinn,Charles Cobbs,Andrew L. Ko,Jeffrey G. Ojemann,Jeffrey G. Ojemann,C. Dirk Keene,Daniel L. Silbergeld,Susan M. Sunkin,Viviana Gradinaru,Gregory D. Horwitz,Hongkui Zeng,Bosiljka Tasic,Ed S. Lein,Jonathan T. Ting,Boaz P. Levi +39 more
TL;DR: Comparative epigenetics is used to identify thousands of human neuronal subclass-specific putative enhancers to regulate viral tools, and 34% of these were conserved in mouse, and could yield brain-wide specificity greater than the most selective marker genes.
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Abstract: Viral genetic tools to target specific brain cell types in humans and non-genetic model organisms will transform basic neuroscience and targeted gene therapy. Here we used comparative epigenetics to identify thousands of human neuronal subclass-specific putative enhancers to regulate viral tools, and 34% of these were conserved in mouse. We established an AAV platform to evaluate cellular specificity of functional enhancers by multiplexed fluorescent in situ hybridization (FISH) and single cell RNA sequencing. Initial testing in mouse neocortex yields a functional enhancer discovery success rate of over 30%. We identify enhancers with specificity for excitatory and inhibitory classes and subclasses including PVALB, LAMP5, and VIP/LAMP5 cells, some of which maintain specificity in vivo or ex vivo in monkey and human neocortex. Finally, functional enhancers can be proximal or distal to cellular marker genes, conserved or divergent across species, and could yield brain-wide specificity greater than the most selective marker genes.
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References
An integrated encyclopedia of DNA elements in the human genome
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities
Sven Heinz,Christopher Benner,Nathanael J. Spann,Eric Bertolino,Yin C. Lin,Peter Laslo,Jason X. Cheng,Cornelis Murre,Harinder Singh,Harinder Singh,Christopher K. Glass +10 more
TL;DR: It is demonstrated in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions.
13K
MEME Suite: tools for motif discovery and searching
Timothy L. Bailey,Mikael Bodén,Fabian A. Buske,Martin C. Frith,Charles E. Grant,Luca Clementi,Jingyuan Ren,Wilfred W. Li,William Stafford Noble +8 more
TL;DR: The popular MEME motif discovery algorithm is now complemented by the GLAM2 algorithm which allows discovery of motifs containing gaps, and all of the motif-based tools are now implemented as web services via Opal.
10.2K
LD score regression distinguishes confounding from polygenicity in genome-wide association studies :
Brendan Bulik-Sullivan,Po-Ru Loh,Hilary K. Finucane,Stephan Ripke,Jian Yang,Nick Patterson,Mark J. Daly,Alkes L. Price,Benjamin M. Neale +8 more
TL;DR: It is found that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size, and the LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control.
Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq
Amit Zeisel,Ana B. Muñoz-Manchado,Simone Codeluppi,Peter Lönnerberg,Gioele La Manno,Anna Juréus,Sueli Marques,Hermany Munguba,Liqun He,Christer Betsholtz,Christer Betsholtz,Charlotte Rolny,Gonçalo Castelo-Branco,Jens Hjerling-Leffler,Sten Linnarsson +14 more
TL;DR: Large-scale single-cell RNA sequencing is used to classify cells in the mouse somatosensory cortex and hippocampal CA1 region and found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex.
3.2K
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