Genetic and Epigenetic Mechanisms That Maintain Hematopoietic Stem Cell Function

Abstract

All hematopoiesis cells develop from multipotent progenitor cells. Hematopoietic stem cells (HSC) have the ability to develop into all blood lineages but also maintain their stemness. Different molecular mechanisms have been identified that are crucial for regulating quiescence and self-renewal to maintain the stem cell pool and for inducing proliferation and lineage differentiation. The stem cell niche provides the microenvironment to keep HSC in a quiescent state. Furthermore, several transcription factors and epigenetic modifiers are involved in this process. These create modifications that regulate the cell fate in a more or less reversible and dynamic way and contribute to HSC homeostasis. In addition, HSC respond in a unique way to DNA damage. These mechanisms also contribute to the regulation of HSC function and are essential to ensure viability after DNA damage. How HSC maintain their quiescent stage during the entire life is still matter of ongoing research. Here we will focus on the molecular mechanisms that regulate HSC function.

Figure 1

Hematopoietic stem cells maintain quiescence through extrinsic and intrinsic signals. The stem cell niche provides signals that regulate HSC quiescence and localization in the niche. DL1 and Notch; CXCL12 and CXCR4; and Wnt and Frizzled. HSC intrinsic transcription factors regulate signaling process to keep HSC in a quiescent stage.

Figure 2

Changes in epigenetic signatures upon HSC differentiation and lineage commitment. Multipotency genes are actively transcribed in hematopoietic stem cells (HSC) to maintain stemness and self-renewal. Promoter and enhancer regions are labelled with activating H3K4 methylation marks (green hexagons) and unmethylated CpG islands (white circles). Key genes, important for lineage commitment and differentiation into progenitor cells of the myeloid (common myeloid progenitors (CMP)) or lymphoid lineage (common lymphoid progenitors (CLP)), are kept in a paused state mainly by the counteracting histone methylation marks H3K27me3 (repressive) and H3K4me3 (activating) in gene regulatory regions, termed as bivalent signatures (yellow hexagons). Upon lineage commitment, multipotency genes are silenced by repressive histone methylation marks (e.g., H3K27m3, H3K9me3, and red hexagons) and partially by gene-specific de novo methylation of CpG islands (grey circles). Upon differentiation bivalent chromatin signatures are resolved depending on lineage choice: paused genes become either activated transcriptionally by accumulation of activating H3K4me3 marks and loss of repressive H3K27me3 or silenced by loss of H3K4me3 and accumulation of H3K27me3 and partially by gene-specific methylation of CpG islands.

Figure 3

Quiescent HSC and proliferating progenitors respond differently to DNA damage (radiation). HSC show a higher expression level of p53 and p21 and they activate the error-prone repair pathway compared to faster cycling progenitors. They show a reduced DDR, NER, and HR response. (NHEJ: nonhomologous end joining; DDR: DNA damage response; NER: nucleotide excision repair; and HR: homologous recombination).