Histone methylation regulator PTIP is required to maintain normal and leukemic bone marrow niches

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 Pparg (Peroxisome proliferator-activated receptor-γ), 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 (LICs) and increased survival upon transplantation. Taken together, our data identify PTIP as a novel epigenetic regulator of osteoclastogenesis that is required for the integrity of the BM niche to sustain both normal hematopoiesis and leukemia.

骨骼对于运动功能、钙储存以及作为终生为机体供给成熟血细胞的造血干细胞（hematopoietic stem cells, HSCs）的寄居场所至关重要。造血干细胞定居于骨骼与骨髓（bone marrow, BM）的交界区域，而此处正是活跃骨重塑发生的位点。尽管骨髓微环境的细胞组分已得到充分表征，但学界对其表观遗传调控机制仍知之甚少。本研究发现，组蛋白甲基化调控因子PTIP（Pax interaction with transcription-activation domain protein-1, PTIP）可通过促进破骨细胞分化，维持骨髓微环境的完整性。PTIP可直接介导破骨细胞生成必需的转录因子——过氧化物酶体增殖物激活受体γ（Peroxisome proliferator-activated receptor-γ, PPARγ）表达所需的染色质构象变化。PTIP基因缺失会导致骨髓内造血干细胞数量急剧减少，并诱导髓外造血的发生。此外，将急性髓系白血病细胞暴露于PTIP缺陷型骨髓微环境中，会使白血病起始细胞（leukemia initiating cells, LICs）的数量降低，同时提升移植后宿主的存活率。综上，本研究数据证实PTIP是一种新型的破骨细胞生成表观遗传调控因子，其对于维持骨髓微环境完整性，进而支持正常造血功能与白血病发生发展均不可或缺。