Hematopoietic stem cell niche generation and maintenance are distinguishable by an epitranscriptomic program

Gao, Longfei; Lee, Heather; Goodman, Joshua H.; Ding, Lei

doi:10.1016/j.cell.2024.03.032

Cited by 3 publications

References 68 publications

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Epigenetics-targeted drugs: current paradigms and future challenges

Dai,

Qiao,

Fang

et al. 2024

Sig Transduct Target Ther

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Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions. Over the past two decades, a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase, histone deacetylase, isocitrate dehydrogenase, and enhancer of zeste homolog 2, have been thoroughly investigated and implemented as therapeutic options, particularly in oncology. Additionally, numerous epigenetics-targeted drugs are undergoing clinical trials, offering promising prospects for clinical benefits. This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs. These include inhibitors, agonists, degraders, and multitarget agents, aiming to identify practical challenges and promising avenues for future research. Ultimately, this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings.

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Epigenetics-targeted drugs: current paradigms and future challenges

Dai,

Qiao,

Fang

et al. 2024

Sig Transduct Target Ther

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Epigenetic modifications in hematopoietic ecosystem: a key tuner from homeostasis to acute myeloid leukemia

Yao,

Guo,

Tian

et al. 2024

Blood Science

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Hematopoietic stem cells (HSCs) maintain homeostasis in the hematopoietic ecosystem, which is tightly regulated at multiple layers. Acute myeloid leukemia (AML) is a severe hematologic malignancy driven by genetic and epigenetic changes that lead to the transformation of leukemia stem cells (LSCs). Since somatic mutations in DNA methylation-related genes frequently occur in AML, DNA methylation is widely altered and functions as a starting engine for initiating AML. Additionally, RNA modifications, especially N6-methyladenosine (m6A), also play an important role in the generation and maintenance of the hematopoietic ecosystem, and AML development requires reprogramming of m6A modifications to facilitate cells with hallmarks of cancer. Given the complex pathogenesis and poor prognosis of AML, it is important to fully understand its pathogenesis. Here, we mainly focus on DNA methylation and RNA m6A modification in hematopoiesis and AML and summarize recent advances in this field.

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Characterization of Multicellular Niches Supporting Hematopoietic Stem Cells Within Distinct Zones

Dong,

Li,

et al. 2024

Preprint

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Previous studies of hematopoietic stem cells (HSCs) primarily focused on single cell-based niche models, yielding fruitful but conflicting findings1–5. Here we report our investigation on the fetal liver (FL) as the primary fetal hematopoietic site using spatial transcriptomics. Our study reveals two distinct niches: the portal-vessel (PV) niche and the sinusoidal niche. The PV niche, composing N-cadherin (N-cad)HiPdgfr+mesenchymal stromal cells (MSCs), endothelial cells (ECs), and N-cadLoAlbumin+hepatoblasts, maintains quiescent and multipotential FL-HSCs. Conversely, the sinusoidal niche, comprising ECs, hepatocytes, and potential macrophages, supports proliferative FL-HSCs biased towards myeloid lineages. Unlike prior reports on the role of Cxcl12, with its depletion from vessel-associated stromal cells leading to 80% of HSCs’ reduction in the adult bone marrow (BM)6,7, depletion ofCxcl12viaCdh2CreERT(encoding N-cad) induces FL-HSCs relocation from the PV to the sinusoidal niches, resulting in an increase of myeloid-biased HSCs. Similarly, we discovered that adult BM encompasses two niches within different zones, each composed of multi-cellular components: trabecular bone area (TBA, or metaphysis) supporting deep-quiescent HSCs, and central marrow (CM, or diaphysis) fostering relatively proliferative HSCs. This study transforms our understanding of niches by shifting from single cell-based to multicellular components within distinct zones, illuminating the intricate regulation of HSCs tailored to their different cycling states.

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Hematopoietic stem cell niche generation and maintenance are distinguishable by an epitranscriptomic program

Cited by 3 publications

References 68 publications

Epigenetics-targeted drugs: current paradigms and future challenges

Epigenetics-targeted drugs: current paradigms and future challenges

Epigenetic modifications in hematopoietic ecosystem: a key tuner from homeostasis to acute myeloid leukemia

Characterization of Multicellular Niches Supporting Hematopoietic Stem Cells Within Distinct Zones

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