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The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
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Multiomics and deep learning dissect regulatory syntax in human development.

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This summary is machine-generated.

Researchers mapped human fetal cell chromatin accessibility and gene expression across 12 organs. This atlas reveals how DNA sequence motifs control gene regulation and cell identity during development.

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Area of Science:

  • Genomics
  • Developmental Biology
  • Computational Biology

Background:

  • Transcription factors regulate cell identity by binding DNA, influencing chromatin accessibility and gene expression.
  • Existing human developmental datasets lack single-cell resolution across multiple organs and modalities.
  • Understanding cis-regulatory elements is crucial for deciphering gene control.

Purpose of the Study:

  • To create a comprehensive single-cell atlas of chromatin accessibility and gene expression in human fetal development.
  • To identify sequence motifs governing chromatin accessibility and transcription factor cooperativity.
  • To explore the role of motif syntax in cell-type-specific gene regulation and interpret genetic variants.

Main Methods:

  • Generated a single-cell atlas from 817,740 fetal cells across 12 organs, profiling chromatin accessibility and gene expression.
  • Utilized deep learning models to predict chromatin accessibility from DNA sequence and identify regulatory motifs.
  • Analyzed motif syntax, including composite motifs, and their impact on transcription factor cooperativity.
  • Interpreted genetic variants using model-based approaches to assess their effects on gene expression.

Main Results:

  • The Human Development Multiomic Atlas comprises 203 cell types and over 1 million candidate cis-regulatory elements with organ-specific enhancer activity.
  • Identified a lexicon of DNA sequence motifs and their 'hard' and 'soft' syntactic rules governing chromatin accessibility.
  • Demonstrated that motif disruption correlates with gene expression changes, revealing regulatory logic.
  • Uncovered ubiquitous motifs that inhibit chromatin accessibility.

Conclusions:

  • Motif syntax dictates cell-type-specific chromatin accessibility and gene regulation during human development.
  • The atlas provides a foundational resource for decoding cis-regulatory logic and interpreting genetic variation.
  • This work deepens our understanding of how transcription factors establish cell identity through precise DNA interactions.