Chromatin Accessibility Shapes Developmental-Specific Lineage Plasticity in Hematopoiesis

Area of Science:

• Hematology
• Developmental Biology
• Epigenetics

Background:

• Cell differentiation is crucial for development and health, regulated by chromatin accessibility.
• Dysregulation of cell differentiation is linked to various diseases.
• Hematopoietic stem and progenitor cells (HSPCs) exhibit different lineage biases based on age, but molecular drivers are unclear.

Purpose of the Study:

• To investigate the molecular differences in chromatin accessibility between fetal and adult human HSPCs.
• To understand how these differences influence lineage potential and differentiation.
• To explore the implications for developmental plasticity and disease susceptibility.

Main Methods:

• Single-cell cultures of hematopoietic stem cells (HSCs) were used to assess differentiation potential.
• Single-cell ATAC-sequencing was performed on first-trimester HSPCs.
• Analysis of transcription factor motif accessibility and regulatory elements.

Main Results:

• Fetal HSCs generated mixed-lineage colonies, while adult HSCs were myeloid-biased.
• Fetal HSPCs lacked enrichment of lineage-specific transcription factor motifs found in adult HSCs.
• A developmental-specific hybrid lympho-myeloid chromatin program was identified in fetal lymphoid progenitors, with reduced PAX5 accessibility.

Conclusions:

• Fetal human HSPCs possess broader lineage plasticity compared to adult HSPCs, characterized by distinct chromatin accessibility patterns.
• Reduced accessibility of key regulatory elements like PAX5 in fetal cells suggests a more plastic lymphoid state.
• This enhanced embryonic lineage plasticity may contribute to prenatal susceptibility to acute lymphoblastic leukemia drivers.