Regulation of B cell development by ABCB7

铁的动态平衡对细胞的基本功能至关重要，铁是许多蛋白质的辅助因子。 调节转录、增殖和生存的物质。游离铁对细胞有毒性。因此，铁的动态平衡 受到严格监管。ABCB7是线粒体内膜上发现的一种完整的膜蛋白， 属于ABC(三磷酸腺苷结合盒)转运蛋白家族。ABCB7转运铁-S-谷胱甘肽 从线粒体到细胞质的中间产物，结合到ISCs(铁硫簇)中。 在Mx1-cre ABCB7条件性基因敲除(CKO)小鼠中诱导的ABCB7缺失导致快速 造血功能衰竭伴多谱系缺陷。然而，ABCB7在特定情况下的功能 造血系还没有被检查过。我们发现MB1-cre ABCB7条件性基因敲除(CKO) 小鼠和CD2-ICRE ABCB7 CKO小鼠表现出严重的B细胞发育障碍，几乎没有IgM+ 产生未成熟的B细胞。CD19-cre或CD23-cre缺失ABCB7对B细胞无影响 发育或外周B细胞动态平衡，表明在B细胞早期对ABCB7有特殊要求 发展并证明ABCB7不仅仅是生存所必需的。在MB1-CRE或CD2-ICRE中 在ABCB7 CKO小鼠中，表达细胞内µHC的B细胞前体细胞减少， 无法下调代理轻链基因。铁是许多酶的辅助因子，这些酶 调节染色质的可及性，包括Tet家族的双加氧酶和大多数组蛋白赖氨酸 去甲基酶(KDM)。因此，缺乏ABCB7可能会扰乱这些酶的功能，改变 随着B淋巴细胞在关键发育阶段的进展，适当调节染色质可及性的能力 检查站。我们推测，B细胞前体细胞中ABCB7的缺失破坏了铁的稳态 通过铁依赖的染色质修饰酶的失调导致发育受阻， 这将在这项提案中进行审查。

Iron homeostasis is critical for basic cellular functions and iron is used as a co-factor by many proteins that regulate transcription, proliferation and survival. Free iron is toxic to cells. Thus, iron homeostasis is tightly regulated. ABCB7 is an integral membrane protein found on mitochondrial inner membranes that belongs to the ABC (ATP-binding cassette) family of transporters. ABCB7 transports Fe-S-glutathione intermediates from the mitochondria to the cytoplasm for incorporation into ISCs (iron sulfur clusters). Inducible deletion of ABCB7 in Mx1-cre ABCB7 conditional knockout (cKO) mice resulted in rapid hematopoietic failure with multi-lineage defects in hematopoiesis. However, the function of ABCB7 in specific hematopoietic lineages has not been examined. We find that both mb1-cre ABCB7 conditional knockout (cKO) mice and CD2-icre ABCB7 cKO mice exhibit a severe block in B cell development with almost no IgM+ immature B cells produced. Deletion of ABCB7 using CD19-cre or CD23-cre had no effect on B cell development or peripheral B cell homeostasis, indicating a specific requirement for ABCB7 early in B cell development and demonstrating that ABCB7 is not simply required for survival. In mb1-cre or CD2-icre ABCB7 cKO mice, there is a decrease in B cell progenitors which express intracellular µHC, and those present are unable to downregulate the surrogate light chain genes. Iron is a co-factor for many enzymes which regulate chromatin accessibility, including the Tet family of dioxygenases and most of the histone lysine demethylases (KDMs). Thus, the absence of ABCB7 may disrupt the function of these enzymes, altering the ability to appropriately regulate chromatin accessibility as B lymphocytes progress through key developmental checkpoints. We hypothesize that disruption of iron homeostasis by deletion of ABCB7 in B cell progenitors leads to a block in their development through dysregulation of iron-dependent chromatin-modifying enzymes, which will be examined in this proposal.