A Chromatin Accessibility Atlas of the Developing Human Telencephalon

Markenscoff-Papadimitriou, Eirene; Whalen, Sean; Przytycki, Pawel F.; Thomas, Reuben; Binyameen, Fadya; Nowakowski, Tomasz J.; Sanders, Stephan; State, Matthew W.; Pollard, Katherine S.; Rubenstein, John L.R.

doi:10.1101/811620

Cited by 3 publications

(2 citation statements)

References 65 publications

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“… A , ATAC-seq (-log 10 P values) and DNase-seq (read depth-normalized signal) of in vitro differentiated cells, commercially available cell lines, and tissues. Fetal LGE is 19th gestational week data from (Markenscoff-Papadimitriou et al 2020). Putamen data are from BOCA (Fullard et al 2018).…”

Section: Resultsmentioning

confidence: 99%

Intronic elements associated with insomnia and restless legs syndrome exhibit cell type-specific epigenetic features contributing to MEIS1 regulation

Lam

Nikolić

Zhao

et al. 2021

Preprint

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A highly evolutionarily conserved MEIS1 intronic region is strongly associated with restless legs syndrome (RLS) and insomnia. To understand its regulatory function, we dissected the region by analyzing chromatin accessibility, enhancer-promoter contacts, DNA methylation, and eQTLs in different human neural cell types and tissues. We observed specific activity with respect to cell type and developmental maturation, indicating a prominent role for distinct highly conserved intronic elements in forebrain inhibitory neuron differentiation. Two elements were hypomethylated in neural cells with higher MEIS1 expression, suggesting a role of enhancer demethylation in gene regulation. MEIS1 eQTLs showed a striking modular chromosomal distribution, with forebrain eQTLs clustering in intron 8/9. CRISPR interference targeting of individual elements in this region attenuated MEIS1 expression, revealing a complex regulatory interplay of distinct elements. In summary, we found that MEIS1 regulation is organized in a modular pattern. Disease-associated intronic regulatory elements control MEIS1 expression with cell type and maturation stage specificity, particularly in the inhibitory neuron lineage. The precise spatiotemporal activity of these elements likely contributes to the pathogenesis of insomnia and RLS.

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Section: Resultsmentioning

confidence: 99%

Intronic elements associated with insomnia and restless legs syndrome exhibit cell type-specific epigenetic features contributing to MEIS1 regulation

Lam

Nikolić

Zhao

et al. 2021

Preprint

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“…More recently, the ATAC-Seq technology has provided straightforward access to the repertoire of open chromatin regions genome-wide, which are often associated with regulatory potential [9]. Hence, ATAC-Seq has been used to generate open chromatin atlases of diverse mammalian tissues [10][11][12][13][14][15][16][17][18]. The fact that a fraction of distant enhancers is rapidly evolving, and cannot readily be identified by sequence similarity searches, emphasizes the importance of generating regulatory element databases in a wide variety of species [16].…”

Section: Introductionmentioning

confidence: 99%

Architecture and evolutionary conservation ofXenopus tropicalisosteoblast-specific regulatory regions shed light on bone diseases and early skeletal evolution

Castillo,

Godoy,

Gilbert

et al. 2023

Preprint

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Understanding the genetic mechanisms underpinning the differentiation of osteoblasts, the bone producing cells, has far reaching implications for skeletal diseases and evolution. To this end, it is crucial to characterize osteoblastic regulatory landscape in a diverse array of distantly-related vertebrate species. By comparing of the ATAC-seq profile of Xenopus tropicalis (Xt) osteoblasts to liver, heart and lung control tissues, we identified 524 promoters and 6,750 distal regions whose chromatin is specifically open in osteoblasts. Nucleotide composition, Gene Ontology, and RNA-Seq confirmed that the identified elements correspond to bona fide osteogenic transcriptional enhancers, and TFBS enrichment revealed a well-conserved regulatory logic with mammals. Amongst the 357 Xt osteoblast-specific enhancers aligning to homologous human loci, 127 map to regions annotated as enhancers. Phenotype predictions based on the genes neighbouring these conserved enhancers are tightly related to impaired skeletal development. In addition, six conserved enhancers are located at loci associated to craniosynostosis (mx2, tcf12), osteopoikilosis (lemd3), osteopenia (gorab), skeletal dysplasia (flnb) and craniofacial abnormalities (gpc4). From an evolutionary perspective, the elephant shark genome aligns to 53 Xt osteoblast-specific enhancers that are also conserved and annotated as enhancers in humans, revealing an ancestral osteogenic role for the ATOH8, IRX3, NFAT, NFIB and MEF2C transcription factors, as well as for the FGF, IHH and BMP/TGFb signalling pathways. As the absence of bone in sharks is a derived feature, we propose that, in this lineage, the osteogenic regulatory network has been maintained for its function in odontoblasts. Our data argues in favour of a common origin for dentine and bone, and provides a glimpse into the key regulatory elements and upstream activators that drove the formation of an ancient type of mineralized tissue in the vertebrates that inhabited the oceans more than 460 million years ago.

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Transcriptional Network Orchestrating Regional Patterning of Cortical Progenitors

Ypsilanti

Pattabiraman

Catta-Preta

et al. 2020

Preprint

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We uncovered a transcription factor (TF) network that regulates cortical regional patterning. Screening the expression of hundreds of TFs in the developing mouse cortex identified 38 TFs that are expressed in gradients in the ventricular zone (VZ). We tested whether their cortical expression was altered in mutant mice with known patterning defects (Emx2, Nr2f1 and Pax6), which enabled us to define a cortical regionalization TF network (CRTFN). To identify genomic programming underlying this network, we performed TF ChIP-seq and chromatin-looping conformation to identify enhancer-gene interactions. To map enhancers involved in regional patterning of cortical progenitors, we performed assays for epigenomic marks and DNA accessibility in VZ cells purified from wild-type and patterning mutant mice. This integrated approach has identified a CRTFN and VZ enhancers involved in cortical regional patterning.

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A Chromatin Accessibility Atlas of the Developing Human Telencephalon

Cited by 3 publications

References 65 publications

Intronic elements associated with insomnia and restless legs syndrome exhibit cell type-specific epigenetic features contributing to MEIS1 regulation

Intronic elements associated with insomnia and restless legs syndrome exhibit cell type-specific epigenetic features contributing to MEIS1 regulation

Architecture and evolutionary conservation ofXenopus tropicalisosteoblast-specific regulatory regions shed light on bone diseases and early skeletal evolution

Transcriptional Network Orchestrating Regional Patterning of Cortical Progenitors

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