Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

Area of Science:

• Genomics
• Developmental Biology
• Epigenetics

Background:

• Genome regulation of transcriptional programs is crucial for organ formation.
• Limited knowledge exists regarding human embryonic development, hindering stem cell differentiation benchmarking and interpretation of noncoding variation pathogenicity.

Purpose of the Study:

• To investigate histone modifications across thirteen human tissues during organogenesis.
• To build a comprehensive overview of differential genome regulation in human development, including gene repression.
• To correlate noncoding mutations with developmental disorders.

Main Methods:

• Histone modification profiling across thirteen human tissues.
• Integration of epigenetic data with transcription data.
• Analysis of gene promoter states and candidate enhancer activity.
• Correlation of patient noncoding mutations with genomic data.

Main Results:

• Nearly 20,000 gene promoters were categorized into distinct regulatory states.
• Key developmental genes are actively repressed outside their specific organ context.
• Tissue-specific and shared transcription factor binding patterns were identified using functional enhancers.
• Over 700 noncoding mutations from developmental disorder patients were linked to novel target genes.

Conclusions:

• The study provides a detailed genomic framework for understanding human organogenesis.
• This framework aids in investigating both normal and abnormal human development.
• The findings offer insights into the regulatory mechanisms underlying developmental disorders.