Identification of determinants of differential chromatin accessibility through a massively parallel genome-integrated reporter assay

Hammelman, Jennifer; Krismer, Konstantin; Banerjee, Budhaditya; Gifford, David K.; Sherwood, Richard I.

doi:10.1101/gr.263228.120

Cited by 16 publications

(8 citation statements)

References 62 publications

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“…To identify putative regulators of maturation, we performed motifenrichment analysis on accessible regions using two distinct but complementary approaches. We used a newly developed convolutional neural network-based method called DeepAccess 65,66 which learns the relationship between primary DNA sequence and chromatin accessibility at different ages and then predicts transcription factor motifs that drive differential chromatin accessibility at one age compared to another. In addition, we used HOMER, a de novo motif discovery method that identifies enriched motifs in provided sets of age-specific accessible peaks 67 (Methods).…”

Section: Motif Analysis Identifies Putative Regulators Of Maturationmentioning

confidence: 99%

Transcriptional dynamics of murine motor neuron maturation in vivo and in vitro

Patel

Hammelman²,

Aziz

et al. 2022

Nat Commun

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Neurons born in the embryo can undergo a protracted period of maturation lasting well into postnatal life. How gene expression changes are regulated during maturation and whether they can be recapitulated in cultured neurons remains poorly understood. Here, we show that mouse motor neurons exhibit pervasive changes in gene expression and accessibility of associated regulatory regions from embryonic till juvenile age. While motifs of selector transcription factors, ISL1 and LHX3, are enriched in nascent regulatory regions, motifs of NFI factors, activity-dependent factors, and hormone receptors become more prominent in maturation-dependent enhancers. Notably, stem cell-derived motor neurons recapitulate ~40% of the maturation expression program in vitro, with neural activity playing only a modest role as a late-stage modulator. Thus, the genetic maturation program consists of a core hardwired subprogram that is correctly executed in vitro and an extrinsically-controlled subprogram that is dependent on the in vivo context of the maturing organism.

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Section: Motif Analysis Identifies Putative Regulators Of Maturationmentioning

confidence: 99%

Transcriptional dynamics of murine motor neuron maturation in vivo and in vitro

Patel

Hammelman²,

Aziz

et al. 2022

Nat Commun

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“…Chromatin accessibility is regulated by numerous epigenetic regulators 27 , 28 . Previous studies have proven that SIRT6, as a key chromatin regulator, remodels chromatin by promoting chromatin relaxation, although it has diverse biological functions, such as genome stability, glucose metabolism, and tumor suppression, through multiple pathways 29 – 34 .…”

Section: Resultsmentioning

confidence: 99%

Sirt6-mediated epigenetic modification of DNA accessibility is essential for Pou2f3-induced thymic tuft cell development

Zhang

Tong

et al. 2022

Commun Biol

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Thymic epithelial cells (TECs) are essential for the production of self-tolerant T cells. The newly identified thymic tuft cells are regulated by Pou2f3 and represent important elements for host type 2 immunity. However, epigenetic involvement in thymic tuft cell development remains unclear. We performed single-cell ATAC-seq of medullary TEC (mTEC) and established single-cell chromatin accessibility profiling of mTECs. The results showed that mTEC III cells can be further divided into three groups (Late Aire 1, 2, and 3) and that thymic tuft cells may be derived from Late Aire 2 cells. Pou2f3 is expressed in both Late Aire 2 cells and thymic tuft cells, while Pou2f3-regulated genes are specifically expressed in thymic tuft cells with simultaneous opening of chromatin accessibility, indicating the involvement of epigenetic modification in this process. Using the epigenetic regulator Sirt6-defect mouse model, we found that Sirt6 deletion increased Late Aire 2 cells and decreased thymic tuft cells and Late Aire 3 cells without affecting Pou2f3 expression. However, Sirt6 deletion reduced the chromatin accessibility of Pou2f3-regulated genes in thymic tuft cells, which may be caused by Sirt6–mediated regulation of Hdac9 expression. These data indicate that epigenetic regulation is indispensable for Pou2f3-mediated thymic tuft cell development.

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“…Hammelman and Gifford created such a deep learning approach and used it for the identification of cell state‐specific TFs in chromatin accessibility data [79, 80]. Their method is part of the framework DeepAccess and is based on an ensemble of convolutional neural networks.…”

Section: Computational Tools For Tfa Inferencementioning

confidence: 99%

Computational tools for inferring transcription factor activity

Hecker,

Lauber,

Behjati Ardakani

et al. 2023

Proteomics

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Transcription factors (TFs) are essential players in orchestrating the regulatory landscape in cells. Still, their exact modes of action and dependencies on other regulatory aspects remain elusive. Since TFs act cell type‐specific and each TF has its own characteristics, untangling their regulatory interactions from an experimental point of view is laborious and convoluted. Thus, there is an ongoing development of computational tools that estimate transcription factor activity (TFA) from a variety of data modalities, either based on a mapping of TFs to their putative target genes or in a genome‐wide, gene‐unspecific fashion. These tools can help to gain insights into TF regulation and to prioritize candidates for experimental validation. We want to give an overview of available computational tools that estimate TFA, illustrate examples of their application, debate common result validation strategies, and discuss assumptions and concomitant limitations.

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Identification of determinants of differential chromatin accessibility through a massively parallel genome-integrated reporter assay

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Cited by 16 publications

References 62 publications

Transcriptional dynamics of murine motor neuron maturation in vivo and in vitro

Transcriptional dynamics of murine motor neuron maturation in vivo and in vitro

Sirt6-mediated epigenetic modification of DNA accessibility is essential for Pou2f3-induced thymic tuft cell development

Computational tools for inferring transcription factor activity

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