Hematopoiesis: a BETter understanding

Plain language summary

Epigenetic modifications are known to be crucial for hematopoietic stem cell (HSC) differentiation, with the BET family member BRD4 playing a vital role in this as an epigenetic reader. In this issue of EMBO reports, Yang et al (2023) demonstrate that the absence of BRD4 leads to senescence in HSCs and hematopoietic progenitor cells (HPCs), affecting the expression of crucial genes involved in myeloid and erythroid development. These data suggest that BRD4 has a protective role in preserving histone tails, thereby sustaining normal HSC/HPC functions.

Epigenetic modifications are crucial for hematopoietic stem cell differentiation. A study in this issue shows that the absence of BRD4 leads to senescence in HSCs and HPCs, affecting the expression of crucial genes involved in myeloid and erythroid development.

Hematopoiesis is the process of generating blood cells through development and throughout an individual's life. HSCs play a central role in creating all mature blood cells, including red blood cells, platelets, myeloid cells (e.g., monocytes and neutrophils), and lymphoid cells (e.g., T cells and B cells) of the immune system (Silver et al, ²⁰²¹). This complex process involves a combination of genetically encoded differentiation programs and interactions with the HSC niche microenvironment, specific transcription factors, and intracellular metabolic changes (Rodrigues et al, ²⁰²⁰). Epigenetic modifications are also crucial for HSC differentiation (Rodrigues et al, ²⁰²⁰; Zhao et al, ²⁰²³). Epigenetics encompasses chromatin‐based reactions that regulate DNA‐templated processes, involving histone modifications, such as acetylation, methylation, and phosphorylation and subsequently gene expression (Zhao et al, ²⁰²³). Histone acetylation promotes an active chromatin state, while histone deacetylases (HDACs) remove acetyl groups, inducing a repressive state. Epigenetic regulators, including writers, readers, and erasers, dynamically influence hematopoiesis and oncogenesis (Rodrigues et al, ²⁰²⁰; Zhao et al, ²⁰²³).

The BET family, including BRD2, BRD3, BRD4, and BRDT, plays a crucial role as epigenetic readers, recognizing acetylated histones and facilitating transcriptional activation. Among the BET proteins, BRD4 has been extensively studied and shown to be critical for gene expression patterns defining stem cell identity and cellular differentiation, including osteoblast and chondrocyte differentiation, adipogenesis, and myogenesis (Dey et al, ²⁰²¹). BRD4 is also essential for the generation of embryonic HSCs and subsequent progenitor development (Dey et al, ²⁰¹⁹). Its absence severely impacts immune system function and leads to developmental defects in HSCs and impaired macrophage proliferation (Dey et al, ²⁰¹⁹). In this issue, Yang et al (2023) extensively investigate various progenitor cell populations and their lineage commitment to myeloid cells in the absence of BRD4. The conditional deletion of BRD4 in the hematopoietic system of 6–8‐week‐old mice results in lethality and a substant increase in HPCs that possess, however, restricted colony‐forming capacity and self‐renewal activity. Furthermore, BRD4 deficiency disrupts the expression of crucial genes involved in the development of myeloid and erythroid cells. Remarkably, the absence of BRD4 leads to senescence, a permanent cell cycle arrest, in HSCs and HPCs. The study shows that the absence of BRD4 induces the expression of the senescence‐associated secretory phenotype (SASP) in HSCs/HPCs, characterized by the secretion of various pro‐inflammatory cytokines, chemokines, growth factors, and matrix‐remodeling proteins by senescent cells (Fig 1).

Figure 1. Role of BRD4 in hematopoiesis.

In hematopoiesis, BRD4 maintains normal HSC/HPC functions by protecting the histone tail. However, when BRD4 is lost, this leads to H3.3 clipping. Clipped H3 (cH3) binds to senescence‐specific genes and promotes the generation of H3K27ac, H3K122ac, and H3K4me3 histone modifications. These modifications render the chromatin more accessible and promote transcription of senescence‐specific genes. Consequently, the absence of BRD4 can result in growth arrest and senescence in HSC/HPCs.

Large H3K27ac regions, an epigenetic mark of active gene regulatory regions found at enhancers and most notably at super‐enhancers (SEs), are associated with essential genes for the self‐renewal of embryonic stem cells (ESCs), cell identity genes, including crucial oncogenes in cancer cells, and senescence phenotypes (Tasdemir et al, ²⁰¹⁶; Dey et al, ²⁰²¹; Grosveld et al, ²⁰²¹). In ESCs, BRD4 binds, as an epigenetic reader, to acetylated histones at SEs of pluripotency genes through its bromodomain, aiding in successful transcription pause release and elongation (Dey et al, ²⁰²¹). Similarly, senescent fibroblasts experience global enhancer landscape remodeling, with BRD4 recruited to newly activated SEs near key SASP genes (Tasdemir et al, ²⁰¹⁶). In senescent fibroblasts, the transcription factor NF‐κB, a key regulator of SASP, is enriched in BRD4‐gained SE regions (Tasdemir et al, ²⁰¹⁶). In apparent contrast, in macrophages in the absence of BRD4, ligand‐induced NF‐κB binding is not reduced; instead, it increases, leading to significant inflammatory responses in BRD4 KO macrophages (Dey et al, ²⁰¹⁹). However, the exact mechanism responsible for this unexpected finding remained unclear until the work of Yang et al (2023), which sheds light on this contrasting observation.

H3.3, a replication‐independent histone H3 variant in mammals, plays a crucial role in maintaining the balanced survival and lineage differentiation of HSCs and HPCs (Guo et al, ²⁰²²). Histone H3.3 and its proteolytic cleaved forms (cH3.3) also act as regulators of cellular senescence (Duarte et al, ²⁰¹⁴). Yang et al (2023) demonstrate that ectopic expression of cH3.3 induces senescence in HSC/HPCs, leading to increased expression of the senescence markers Cdkn1a (p21) and Cdkn2a (p16) (Fig 1). They find that BRD4 protects against histone H3 clipping, particularly at genomic loci of senescence‐related genes, thereby maintaining normal HSC/HPC functions. The loss of BRD4 leads to the induction of H3.3 clipping, resulting in its binding to senescence‐specific gene loci and the generation of H3K27ac, H3K122ac, and H3K4me3 modifications, thus enhancing chromatin accessibility and promoting the transcription of senescence‐specific genes. BRD4‐deficient cells show higher cH3 occupancy at SASP gene loci, linking cH3 to SASP genes. These findings shed light on the delicate balance between normal and pathological hematopoiesis and how this is influenced by cH3.3 and BRD4.

Overall, the study by Yang et al (2023) provides significant insights into the role of BRD4 in hematopoietic stem cells and progenitor cells and its potential involvement in senescence and inflammatory processes. Further research in this area may have important implications for understanding hematologic diseases and the development of targeted therapies.

EMBO reports (2023) 24: e57927