Dynamic Transcriptional and Epigenetic Changes Drive Cellular Plasticity in the Liver.
Dynamic Transcriptional and Epigenetic Changes Drive Cellular Plasticity in the Liver.
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DOI：
10.1002/hep.31704
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Stanger BZ
中科院分区：
文献类型：
--
作者：
Merrell AJ;Peng T;Li J;Sun K;Li B;Katsuda T;Grompe M;Tan K;Stanger BZ
肝损伤后，一部分肝细胞在称为胆汁重编程的过程中采用胆管上皮细胞（BEC）的特征。本研究的目的是阐明伴随细胞身份的这种戏剧性转变的分子事件。我们应用批量RNA测序（RNA-seq），单细胞RNA测序（scRNA-seq）和高通量测序转座酶可及染色质测定（ATAC-seq）技术来确定与胆汁重编程相关的表观遗传和转录变化。此外，我们通过分析在下游TGFβ信号传导组分Smad 4中肝细胞特异性缺失的小鼠中经历重编程的细胞来检查TGFβ信号传导的作用。胆汁重编程遵循改变基因表达的定型模式，包括胆汁基因的强烈诱导和肝细胞基因的较弱抑制。这些基因表达的变化伴随着相应的修改在染色质水平。虽然一些重编程细胞具有“完全分化”BEC的分子特征，但大多数缺乏一些胆管特征，并保留了一些肝细胞特征。令人惊讶的是，Smad 4突变小鼠的单细胞分析显示重编程的显着增加。肝细胞在胆汁重编程过程中发生广泛的染色质和转录变化，导致表观遗传和基因表达谱与天然BEC相似但不同。重编程涉及胆汁分子特征的进行性积累，而没有离散的中间体。有趣的是，通过Smad 4的典型TGFβ信号传导似乎限制了胆管重编程，表明TGFβ可以促进或抑制胆管分化，这取决于参与该途径的下游组分。这项工作对成人肝脏中新的BEC和胆管的形成具有意义。
Following liver injury, a fraction of hepatocytes adopt features of biliary epithelial cells (BECs) in a process known as biliary reprogramming. The aim of this study was to elucidate the molecular events accompanying this dramatic shift in cellular identity. We applied the techniques of bulk RNA-sequencing (RNA-seq), single cell RNA-sequencing (scRNA-seq), and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to define the epigenetic and transcriptional changes associated with biliary reprogramming. In addition, we examined the role of TGFβ signaling by profiling cells undergoing reprogramming in mice with hepatocyte-specific deletion in the downstream TGFβ signaling component Smad4. Biliary reprogramming followed a stereotyped pattern of altered gene expression consisting of robust induction of biliary genes and weaker repression of hepatocyte genes. These changes in gene expression were accompanied by corresponding modifications at the chromatin level. While some reprogrammed cells had molecular features of “fully differentiated” BECs, most lacked some biliary characteristics and retained some hepatocyte characteristics. Surprisingly, single cell analysis of Smad4 mutant mice revealed a dramatic increase in reprogramming. Hepatocytes undergo widespread chromatin and transcriptional changes during biliary reprogramming, resulting in epigenetic and gene expression profiles that are similar to, but distinct from, native BECs. Reprogramming involves a progressive accumulation of biliary molecular features without discrete intermediates. Paradoxically, canonical TGFβ signaling through Smad4 appears to constrain biliary reprogramming, indicating that TGFβ can either promote or inhibit biliary differentiation depending on which downstream components of the pathway are engaged. This work has implications for the formation of new BECs and bile ducts in the adult liver.
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影响因子：
64.8
作者：
Halpern KB;Shenhav R;Matcovitch-Natan O;Toth B;Lemze D;Golan M;Massasa EE;Baydatch S;Landen S;Moor AE;Brandis A;Giladi A;Avihail AS;David E;Amit I;Itzkovitz S
通讯作者：
Itzkovitz S
影响因子：
46.9
作者：
Azuma, Hisaya;Paulk, Nicole;Grompe, Markus
通讯作者：
Grompe, Markus
影响因子：
64.8
作者：
Qian, Li;Huang, Yu;Srivastava, Deepak
通讯作者：
Srivastava, Deepak
DOI：
10.1126/science.1242281
发表时间：
2014-06-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Blanpain C;Fuchs E
通讯作者：
Fuchs E
影响因子：
2.7
作者：
Poncy, Alexis;Antoniou, Aline;Lemaigre, Frederic P.
通讯作者：
Lemaigre, Frederic P.