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Multi-scale chromatin footprinting reveals wide-spread alterations to the structure of DNA regulatory elements [BAC]

ABSTRACT: Cis-regulatory elements (CREs) are bound by diverse chromatin-associated proteins, cooperate to establish gene expression, and change in structure over time to alter cell fate and function1–3. Here, we develop a footprinting framework that uses deep learning to correct Tn5 sequence bias, improving accuracy and reducing false positives. This framework additionally identifies the interaction of DNA with objects of various sizes. Using these ‘multi-scale footprints’ we find that transcription factor (TF) binding occurs at well-defined distances from nucleosomes. Further, we demonstrate that multi-scale footprints, which include the positions of nucleosomes, enable more accurate inference of TF binding. Using multi-scale footprinting with single-cell multi-omics, we discover wide-spread structural and functional changes of CREs across hematopoiesis, wherein nucleosomes slide, expose DNA for TF binding, and promote gene expression. Finally, we apply this single-cell and footprint approach to characterize age-associated structural changes to CREs within hematopoietic stem cells and identify a spectrum of cells harboring age-associated changes to the epigenome. Interestingly, we find extensive changes to the structure of CREs upon aging, with many age-associated changes altering CRE structure while preserving overall accessibility. Collectively, we reveal the dynamics and functional importance of CRE structure, highlighting changes to gene regulation at single-cell and single-base-pair resolution.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216403 | GEO | 2023/03/29

REPOSITORIES: GEO

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Multi-scale chromatin footprinting reveals wide-spread alterations to the structure of DNA regulatory elements [Human BMMC ATAC]

Project description:Cis-regulatory elements (CREs) are bound by diverse chromatin-associated proteins, cooperate to establish gene expression, and change in structure over time to alter cell fate and function1–3. Here, we develop a footprinting framework that uses deep learning to correct Tn5 sequence bias, improving accuracy and reducing false positives. This framework additionally identifies the interaction of DNA with objects of various sizes. Using these ‘multi-scale footprints’ we find that transcription factor (TF) binding occurs at well-defined distances from nucleosomes. Further, we demonstrate that multi-scale footprints, which include the positions of nucleosomes, enable more accurate inference of TF binding. Using multi-scale footprinting with single-cell multi-omics, we discover wide-spread structural and functional changes of CREs across hematopoiesis, wherein nucleosomes slide, expose DNA for TF binding, and promote gene expression. Finally, we apply this single-cell and footprint approach to characterize age-associated structural changes to CREs within hematopoietic stem cells and identify a spectrum of cells harboring age-associated changes to the epigenome. Interestingly, we find extensive changes to the structure of CREs upon aging, with many age-associated changes altering CRE structure while preserving overall accessibility. Collectively, we reveal the dynamics and functional importance of CRE structure, highlighting changes to gene regulation at single-cell and single-base-pair resolution.

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Project description:The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ~8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ~95% similar with that derived from human TF footprints. However, only ~20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity. We performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ~8.6 million transcription factor (TF) occupancy sites at nucleotide resolution.

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