Stable Chromatin Binding Prevents FoxA Acetylation, Preserving FoxA Chromatin Remodeling
Stable Chromatin Binding Prevents FoxA Acetylation, Preserving FoxA Chromatin Remodeling
复制标题
DOI：
10.1074/jbc.m109.063149
复制
发表时间：
2010-01-01
影响因子：
4.8
通讯作者：
Cirillo, Lisa Ann
中科院分区：
文献类型：
--
作者：
Kohler, Sarah;Cirillo, Lisa Ann
FoxA1-3（以前称为 HNF3 α、-β 和 -γ）是叉头转录因子 FoxA 亚家族的成员，在多种组织（包括肝脏和胰腺）中充当初始染色质结合和染色质重塑因子。尽管 FoxA 因子在发育和代谢中发挥重要作用，但其调节机制尚不清楚。本研究探讨了乙酰化在调节 FoxA 染色质结合和重塑中的潜在作用。通过计算机分析，我们在 FoxA1 中鉴定出了 11 个假定的 p300 乙酰化位点，其中 5 个位于其翼状螺旋 DNA 结合结构域的翼 1 和翼 2 内。这些多肽结构稳定了 FoxA DNA 和染色质的结合，并且我们已经证明乙酰化会减弱 FoxA 与 DNA 的结合并削弱其重塑染色质的能力。 FoxA 乙酰化受到染色质结合的抑制。我们提出了一个模型，通过稳定的染色质结合保护 FoxA DNA 结合结构域免于乙酰化，从而在缺乏细胞外线索的情况下保留 FoxA 因子的染色质结合和重塑。
FoxA1-3 (formerly HNF3 alpha, -beta, and -gamma), members of the FoxA subfamily of forkhead transcription factors, function as initial chromatin-binding and chromatin-remodeling factors in a variety of tissues, including liver and pancreas. Despite essential roles in development and metabolism, regulation of FoxA factors is not well understood. This study examines a potential role for acetylation in the regulation of FoxA chromatin binding and remodeling. Using in silico analysis, we have identified 11 putative p300 acetylation sites within FoxA1, five of which are located within wings 1 and 2 of its winged-helix DNA-binding domain. These polypeptide structures stabilize FoxA DNA and chromatin binding, and we have demonstrated that acetylation attenuates FoxA binding to DNA and diminishes its ability to remodel chromatin. FoxA acetylation is inhibited by chromatin binding. We propose a model whereby stable chromatin binding protects the FoxA DNA-binding domain from acetylation to preserve chromatin binding and remodeling by FoxA factors in the absence of extracellular cues.