Uncovering the role of KDM5C and RBM25 in normal hematopoiesis

Hematopoiesis is a dynamic and complex process initiated and maintained by hematopoietic stem cells (HSC). HSCs have the ability to both self-renew and differentiate into mature blood cells across all hematopoietic lineages, which in turn are involved in crucial processes such as immune defense, oxygen transport and tissue repair. The balance between self-renewal and differentiation of HSCs is achieved by precise control of gene regulatory programs that ensure proper cell fate and identity. In contrast, dysregulation of gene expression in hematopoiesis can lead to defects in hematopoietic development as well as hematological malignancies such as leukemia. Examples of proteins that can contribute to the regulation of gene expression during normal hematopoiesis are epigenetic and splicing factors.
Thus, this thesis aimed at investigating the roles of epigenetic factor: KDM5C and splicing factor: RBM25 during normal hematopoiesis. Here, we used conditional knockout mouse models to individually characterize the loss of Kdm5c and Rbm25 in the murine hematopoietic system.
First, we demonstrated in vivo that loss of histone demethylase KDM5C results in an accelerated exhaustion of HSCs mediated by increased DNA damage, apoptosis and hyperproliferation. We established an HSC intrinsic role of KDM5C by several methods including single-cell RNA sequencing and ex vivo growth. Ultimately, as a general mechanism in normal hematopoiesis, we show that KDM5C is involved in the transcriptional repression of bivalent and repressed promoters.
Collectively, this work revealed that KDM5C facilitates gene repression required for the maintenance of HSC.
Second, we demonstrated a fundamental role of splicing factor RBM25 across multiple hematopoietic lineages. Accordingly, the complete deletion of RBM25 resulted in a severe and rapid collapse of the murine hematopoietic system. We further showed that RBM25 is also required for the survival of mouse embryonic stem cells. In contrast, we demonstrated that partial deletion of RBM25 shows no detectable impact on hematopoiesis during both long periods of observation and under hematopoietic stress. Overall, we revealed that RBM25 is required for the maintenance of normal hematopoiesis although not in a dose-dependent manner.
In summary, this thesis has provided novel insights into the roles of KDM5C and RBM25 in regulating normal hematopoiesis. The work presented in this thesis contributes to the knowledge of key players involved in the maintenance of HSC and hematopoiesis.