Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs

Area of Science:

• * Epigenetics and Molecular Biology
• * Developmental Biology
• * Hematopoiesis

Background:

• * Blood cell production is a complex, hierarchical process involving multiple cell divisions and molecular events.
• * Understanding the integration of environmental signals, transcription factors, and epigenetic modifications is crucial but incomplete.
• * Comprehensive reference epigenomes of human cord blood subsets were generated to address this knowledge gap.

Purpose of the Study:

• * To investigate the epigenetic landscape of human cord blood progenitor cells.
• * To identify key epigenetic modifications involved in hematopoietic cell differentiation.
• * To understand the role of chromatin states in lymphoid and myeloid fate decisions.

Main Methods:

• * Generation of comprehensive reference epigenomes for 8 phenotypically defined subsets of normal human cord blood.
• * Analysis of H3K27me3 density and its patterns in different cell types.
• * Investigation of DNA methylation status of active enhancers during differentiation.
• * In vitro experiments inhibiting polycomb group members to assess their impact on cell fate decisions.

Main Results:

• * A striking contraction of H3K27me3 density was observed in differentiated myelo-erythroid cells.
• * Distinct progenitor cell types showed a conserved repressive H3K27me3 signature with large organized chromatin K27-modification domains.
• * This H3K27me3 signature was retained in mature lymphoid cells but lost in monocytes and erythroblasts.
• * Inhibition of polycomb group members influenced lymphoid and myeloid fate decisions in neonatal hematopoietic progenitors.
• * A majority of active enhancers were present in early progenitors, with dynamic DNA methylation changes during differentiation.

Conclusions:

• * Primitive human hematopoietic cells possess a unique H3K27me3 signature essential for maintaining lymphoid and myeloid cell fates.
• * The loss of this repressive H3K27me3 signature during terminal differentiation is a critical event.
• * Control of these chromatin state changes is integral to normal hematopoietic progenitor cell differentiation and fate determination.