Trim28 plays an indispensable role in maintaining functions and transcriptional integrity of hematopoietic stem cells

Abstract

Hematopoiesis is a complex process that is regulated at multiple levels and through both intrinsic and extrinsic regulators. Trim28 is a multidomain protein that functions as a transcription factor and E3 ubiquitin ligase. Recent studies have established the pivotal roles of Trim28 in a variety of pathophysiologic processes including inflammation, autoimmune disorders, viral pathogenesis, cancer, tumor microenvironment and epithelial-to- mesenchymal transition. However, importance of Trim28 in early hematopoiesis, particularly in the maintenance and functions of hematopoietic stem and progenitor cells (HSPCs), remains largely unknown. In the present study, we identified Trim28 as a critical regulator of self-renewal, quiescence, and functions of hematopoietic stem cells (HSC). Conditional ablation of Trim28 in HSCs leads to perinatal lethality, due to pancytopenia within the hematopoietic lineage. Loss of Trim28 in HSCs affects their differentiation into myeloid-, erythroid-, and lymphoid- lineages. Trim28 deletion leads to altered frequencies and absolute numbers of HSCs, Multipotent Progenitors (MPPs) and lineage committed progenitors in the bone marrow (BM). Primary- and secondary- BM transplantation studies identified an indispensable and a cell-intrinsic role for Trim28 in HSCs. Mechanistic studies identified hyperproliferation of HSPCs and deregulated expression of cell cycle regulators in HSPCs. Strikingly, gene expression studies demonstrated that Trim28 deficiency impairs the transcriptional landscape and transcription factors signatures of HSPCs. In essence, these studies highlight a previously unknown role for Trim28 in the maintenance, functions, and multi-lineage differentiation of HSPCs.