The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine cell specification and postnatal β-cell maturation
The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine cell specification and postnatal β-cell maturation
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DOI：
10.1242/dev.143123
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发表时间：
2017-01-15
期刊：
影响因子：
4.6
通讯作者：
Wright, Christopher V. E.
中科院分区：
文献类型：
--
作者：
Yang, Yu-Ping;Magnuson, Mark A.;Wright, Christopher V. E.
转录因子Pdx1在胰腺器官发生的多个方面都是必需的。目前尚不清楚Pdx1的表达和功能在多大程度上依赖于通过5'保守顺式调控区域的反式激活，特别是哺乳动物特异性区域II（-2139至-1958 bp）是否影响器官发生的次要或主要方面。研究表明，II区是体内上皮多能细胞、新生内分泌祖细胞、分化和成熟β细胞中内分泌选择性转录的主要效应因子。Pdx1（Delta AREAII/-）小鼠表现出内分泌祖细胞和后代激素产生细胞的大量减少，表明Area II活性是在多能细胞群体中建立有效的内分泌谱系规范程序的基础。在已经指定的表达neurog3的内分泌祖细胞中创建区域ii缺失状态，相对于胰岛素(+)β细胞，胰高血糖素(+)α的比例增加，这与内分泌祖细胞中决定α细胞的Arx基因的转录和表观遗传抑制有关。还有胰高血糖素和胰岛素共表达细胞，以及不能成熟的细胞。在细胞进入胰岛素表达阶段后产生Pdx1（Delta AREAII）状态，导致未成熟和功能失调的胰岛β细胞在重要的β细胞相关基因中携带异常染色质标记。因此，通过Area II的跨调控整合介导了范围广泛的祖细胞和β细胞特异性Pdx1功能。
The transcription factor Pdx1 is required for multiple aspects of pancreatic organogenesis. It remains unclear to what extent Pdx1 expression and function depend upon trans-activation through 5' conserved cis-regulatory regions and, in particular, whether the mammal-specific Area II (-2139 to -1958 bp) affects minor or major aspects of organogenesis. We show that Area II is a primary effector of endocrine-selective transcription in epithelial multipotent cells, nascent endocrine progenitors, and differentiating and mature beta cells in vivo. Pdx1(Delta AREAII/-) mice exhibit a massive reduction in endocrine progenitor cells and progeny hormone-producing cells, indicating that Area II activity is fundamental to mounting an effective endocrine lineage-specification program within the multipotent cell population. Creating an Area II-deleted state within already specified Neurog3expressing endocrine progenitor cells increased the proportion of glucagon(+) alpha relative to insulin(+) beta cells, associated with the transcriptional and epigenetic derepression of the alpha-cell-determining Arx gene in endocrine progenitors. There were also glucagon and insulin co-expressing cells, and beta cells that were incapable of maturation. Creating the Pdx1(Delta AREAII) state after cells entered an insulin-expressing stage led to immature and dysfunctional islet beta cells carrying abnormal chromatin marking in vital beta-cell-associated genes. Therefore, trans-regulatory integration through Area II mediates a surprisingly extensive range of progenitor and beta-cell-specific Pdx1 functions.