Histone methylation regulator PTIP is required to maintain normal and leukemic bone marrow niches
Histone methylation regulator PTIP is required to maintain normal and leukemic bone marrow niches
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DOI：
10.1073/pnas.1806019115
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发表时间：
2018-10-23
影响因子：
11.1
通讯作者：
Santos, Margarida A.
中科院分区：
文献类型：
--
作者：
Das, Prosun;Veazey, Kylee J.;Santos, Margarida A.
骨骼对于运动、钙储存和容纳造血干细胞（HSC）至关重要，造血干细胞在整个生命过程中为身体提供成熟的血细胞。HSC位于骨和骨髓（BM）的界面，在那里发生主动骨重建。虽然BM生态位的细胞成分已经被表征，但对其表观遗传调控知之甚少。在这里，我们发现，组蛋白甲基化调节PTIP（Pax与转录激活结构域蛋白-1的相互作用）是必需的，以维持BM生态位的完整性，促进破骨细胞分化。PTIP直接促进Ppar γ（过氧化物酶体增殖物激活受体-γ）表达所需的染色质变化，Ppar γ是破骨细胞生成所必需的转录因子。PTIP缺失导致骨髓中HSC的急剧减少并诱导髓外造血。此外，急性髓性白血病细胞暴露于PTIP缺陷的BM微环境导致白血病起始细胞的减少和移植后存活率的增加。总之，我们的数据确定PTIP作为破骨细胞生成的表观遗传调节因子，其是维持正常造血和白血病的BM生态位的完整性所必需的。
The bone is essential for locomotion, calcium storage, and harboring the hematopoietic stem cells (HSCs) that supply the body with mature blood cells throughout life. HSCs reside at the interface of the bone and bone marrow (BM), where active bone remodeling takes place. Although the cellular components of the BM niche have been characterized, little is known about its epigenetic regulation. Here we find that the histone methylation regulator PTIP (Pax interaction with transcription-activation domain protein-1) is required to maintain the integrity of the BM niche by promoting osteoclast differentiation. PTIP directly promotes chromatin changes required for the expression of Ppar gamma (peroxisome proliferator-activated receptor-gamma), a transcription factor essential for osteoclastogenesis. PTIP deletion leads to a drastic reduction of HSCs in the BM and induces extramedullary hematopoiesis. Furthermore, exposure of acute myeloid leukemia cells to a PTIP-deficient BM microenvironment leads to a reduction in leukemia-initiating cells and increased survival upon transplantation. Taken together, our data identify PTIP as an epigenetic regulator of osteoclastogenesis that is required for the integrity of the BM niche to sustain both normal hematopoiesis and leukemia.