Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis.
Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis.
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DOI：
10.1038/nature12687
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发表时间：
2013-12-05
期刊：
影响因子：
64.8
通讯作者：
Artis, David
中科院分区：
文献类型：
--
作者：
Alenghat, Theresa;Osborne, Lisa C.;Saenz, Steven A.;Kobuley, Dmytro;Ziegler, Carly G. K.;Mullican, Shannon E.;Choi, Inchan;Grunberg, Stephanie;Sinha, Rohini;Wynosky-Dolfi, Meghan;Snyder, Annelise;Giacomin, Paul R.;Joyce, Karen L.;Hoang, Tram B.;Bewtra, Meenakshi;Brodsky, Igor E.;Sonnenberg, Gregory F.;Bushman, Frederic D.;Won, Kyoung-Jae;Lazar, Mitchell A.;Artis, David
炎症性肠病（IBD）和其他慢性炎症性疾病的发展和严重程度可能受到宿主遗传和环境因素的影响，包括来自肠道细菌的信号。然而，整合这些不同线索的机制仍不明确。在这里，我们证明了肠上皮细胞特异性缺失表观基因组修饰酶组蛋白去乙酰化酶3的小鼠（HDAC 3 ΔIEC小鼠）表现出广泛的IEC内在基因表达失调，包括与抗菌防御相关的基因的基础表达降低。关键的是，常规饲养的HDAC 3 ΔIEC小鼠表现出潘氏细胞损失、IEC功能受损和肠道细菌组成改变。此外，HDAC 3 ΔIEC小鼠表现出对肠道损伤和炎症的易感性显著增加，表明HDAC 3的上皮表达在维持肠道稳态中起着核心作用。将HDAC 3 ΔIEC小鼠重新衍生到无菌条件下，发现在没有肠道细菌的情况下，失调的IEC基因表达、潘氏细胞稳态和肠屏障功能在很大程度上得到恢复。虽然IEC内在HDAC 3表达调节这些复杂表型的具体机制仍有待阐明，但这些数据表明HDAC 3是整合肠道细菌来源的信号以校准建立正常宿主-肠道关系和维持肠道稳态所需的上皮细胞反应的关键因子。
The development and severity of inflammatory bowel diseases (IBD) and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3ΔIEC mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defense. Critically, conventionally-housed HDAC3ΔIEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3ΔIEC mice exhibited significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 plays a central role in maintaining intestinal homeostasis. Rederivation of HDAC3ΔIEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis, and intestinal barrier function were largely restored in the absence of commensal bacteria. While the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be elucidated, these data indicate that HDAC3 is a critical factor that integrates commensal bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis.
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影响因子：
64.8
作者：
Alenghat, Theresa;Meyers, Katherine;Mullican, Shannon E.;Leitner, Kirstin;Adeniji-Adele, Adetoun;Avila, Jacqueline;Bucan, Maja;Ahima, Rexford S.;Kaestner, Klaus H.;Lazar, Mitchell A.
通讯作者：
Lazar, Mitchell A.
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
64.8
作者：
Devkota, Suzanne;Wang, Yunwei;Musch, Mark W.;Leone, Vanessa;Fehlner-Peach, Hannah;Nadimpalli, Anuradha;Antonopoulos, Dionysios A.;Jabri, Bana;Chang, Eugene B.
通讯作者：
Chang, Eugene B.
DOI：
10.1126/science.1198125
发表时间：
2011-03-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Feng D;Liu T;Sun Z;Bugge A;Mullican SE;Alenghat T;Liu XS;Lazar MA
通讯作者：
Lazar MA
影响因子：
64.5
作者：
Cadwell K;Patel KK;Maloney NS;Liu TC;Ng AC;Storer CE;Head RD;Xavier R;Stappenbeck TS;Virgin HW
通讯作者：
Virgin HW