YY1 knockout in pro-B cells impairs lineage commitment, enabling unusual hematopoietic lineage plasticity

Area of Science:

• * Hematopoiesis and immunology
• * Molecular and cellular biology

Background:

• * B-cell development is a tightly regulated process involving distinct developmental stages.
• * The pro-B-cell stage is critical for commitment to the B-cell lineage.
• * YY1 (Yin and Yang 1) is a pleiotropic transcription factor with known roles in gene activation and repression.

Purpose of the Study:

• * To investigate the role of YY1 in B-cell lineage commitment.
• * To explore the potential of YY1-deficient pro-B cells to adopt alternative cell fates.
• * To elucidate the molecular mechanisms underlying YY1's function in lineage commitment.

Main Methods:

• * YY1 knockout in pro-B cells.
• * In vitro differentiation assays using OP9-DL4 co-culture system.
• * In vivo transplantation into Rag1-deficient mice.
• * Single-cell RNA sequencing (scRNA-seq).
• * RNA sequencing (RNA-seq), ChIP-sequencing (ChIP-seq), and scATAC-sequencing (scATAC-seq).

Main Results:

• * YY1 knockout at the pro-B-cell stage abrogated B-cell lineage commitment.
• * YY1-deficient pro-B cells differentiated into T-lineage cells in vitro and in vivo.
• * scRNA-seq revealed extensive lineage plasticity in YY1-deficient pro-B cells, with cells adopting profiles of multiple hematopoietic lineages.
• * YY1 regulates chromatin accessibility of alternative lineage genes, facilitating lineage switching.

Conclusions:

• * YY1 is indispensable for establishing and maintaining B-cell lineage commitment.
• * Loss of YY1 function confers remarkable plasticity upon pro-B cells, enabling their differentiation into diverse hematopoietic lineages.
• * YY1 likely acts as a master regulator of lineage commitment by controlling chromatin accessibility and gene expression programs.