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BCLAF1 restrains stress responses in hematopoietic stem cells to support expansion and repopulation [CUT&RUN]

ABSTRACT: Hematopoietic stem cells (HSC) rapidly expand during fetal development and after stress. Here, we identify BCLAF1 as a regulator of HSC repopulation activity with functions in propagation of fetal HSCs and hematopoietic reconstitution after stem cell transplantation. Using mice with hematopoietic-specific and inducible deletion of Bclaf1, we find that BCLAF1 promotes fetal HSC expansion but is dispensible for maintenance of adult HSCs at steady state. Loss of BCLAF1 in either fetal or adult HSCs significantly impairs their self-renewal and multi-lineage reconstitution activity after stem cell transplantation. Single-cell RNA sequencing of fetal hematopoietic progenitors reveals that loss of BCLAF1 reduces long-term HSCs and restrains expression of stress response genes. BCLAF1 associates with chromatin throughout the genome of fetal and adult hematopoietic cells, likely through indirect mechanisms, to regulate transcriptional programs. These results establish a novel function for the transcriptional regulator BCLAF1 in limiting stress responses in HSCs to preserve their expansion during embryogenesis and after stem cell transplant.

ORGANISM(S): Mus musculus

PROVIDER: GSE279223 | GEO | 2025/08/20

REPOSITORIES: GEO

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Project description:Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from the AGM, FL and BM. Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive line from Fetal Calvaria (OP9) and non-supportive stromal clones from fetal liver (BFC). Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from fetal liver. We took advantage of stromal clones established from the AGM, FL and BM and tested for their ability to support or not HSCs ex vivo. RNA were extracted from confluent stromal cultures or sorted cells and used for hybridization of Affymetrix (mouse gene 1.0 ST) microarrays.

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BCLAF1 restrains stress responses in hematopoietic stem cells to support expansion and repopulation [CUT&RUN]

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