The Laboratory of Biology, The University of Ioannina, Faculty of Medicine, 45 110 Ioannina, Greece.
Stem Cell and Chromatin Group, The Institute of Molecular Biology and Biotechnology, Biomedical Division, FORTH-ITE, Greece; The Laboratory of Biology, The University of Ioannina, Faculty of Medicine, 45 110 Ioannina, Greece.
Biochim Biophys Acta Gene Regul Mech. 2017 Jun;1860(6):661-673. doi: 10.1016/j.bbagrm.2017.01.009. Epub 2017 Jan 20.
Cell differentiation is associated with progressive immobilization of chromatin proteins, expansion of heterochromatin, decrease of global transcriptional activity and induction of lineage-specific genes. However, how these processes relate to one another remains unknown. We show here that the heterochromatic domains of mouse embryonic stem cells (ESCs) are dynamically distinct and possesses a mosaic sub-structure. Although random spatio-temporal fluctuations reshuffle continuously the chromatin landscape, each heterochromatic territory maintains its dynamic profile, exhibiting robustness and resembling a quasi-steady state. Transitions towards less dynamic states are detected sporadically as ESCs downregulate Nanog and exit the self-renewal phase. These transitions increase in frequency after lineage-commitment, but evolve differently depending on cellular context and transcriptional status. We propose that chromatin remodeling is a step-wise process, which involves stochastic de-stabilization of regional steady states and formation of new dynamic ensembles in coordination to changes in the gene expression program.
细胞分化与染色质蛋白的逐渐固定、异染色质的扩展、整体转录活性的降低以及谱系特异性基因的诱导有关。然而，这些过程之间的关系尚不清楚。我们在这里表明，小鼠胚胎干细胞（ESCs）的异染色质域是动态不同的，并具有镶嵌的亚结构。尽管随机的时空波动不断改变染色质景观，但每个异染色质区域都保持其动态特征，表现出稳健性，类似于准稳态。随着 ESCs 下调 Nanog 并退出自我更新阶段，偶尔会检测到向动态性较低的状态的转变。这些转变的频率在谱系分化后增加，但由于细胞环境和转录状态的不同而以不同的方式演变。我们提出，染色质重塑是一个逐步的过程，涉及区域稳态的随机不稳定性和新的动态集合的形成，以协调基因表达程序的变化。
