LeBlanc Lucy, Kim Mijeong, Kambhampati Aparna, Son Albert J, Ramirez Nereida, Kim Jonghwan
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
Interdisciplinary Life Sciences Graduate Program, The University of Texas at Austin, Austin, TX 78712, USA.
iScience. 2021 Dec 1;25(1):103541. doi: 10.1016/j.isci.2021.103541. eCollection 2022 Jan 21.
Although cell density is known to affect numerous biological processes including gene expression and cell fate specification, mechanistic understanding of what factors link cell density to global gene regulation is lacking. Here, we reveal that the expression of thousands of genes in mouse embryonic stem cells (mESCs) is affected by cell seeding density and that low cell density enhances the efficiency of differentiation. Mechanistically, β-catenin is localized primarily to adherens junctions during both self-renewal and differentiation at high density. However, when mESCs differentiate at low density, β-catenin translocates to the nucleus and associates with Tcf7l1, inducing co-occupied lineage markers. Meanwhile, Esrrb sustains the expression of pluripotency-associated genes while repressing lineage markers at high density, and its association with DNA decreases at low density. Our results provide new insights into the previously neglected but pervasive phenomenon of density-dependent gene regulation.
尽管已知细胞密度会影响包括基因表达和细胞命运决定在内的众多生物学过程，但对于哪些因素将细胞密度与全局基因调控联系起来，仍缺乏机制上的理解。在这里，我们揭示了小鼠胚胎干细胞（mESCs）中数千个基因的表达受细胞接种密度的影响，并且低细胞密度可提高分化效率。从机制上讲，在高密度的自我更新和分化过程中，β-连环蛋白主要定位于黏着连接。然而，当mESCs在低密度下分化时，β-连环蛋白会转移到细胞核并与Tcf7l1结合，诱导共同占据的谱系标记。同时，Esrrb在高密度时维持多能性相关基因的表达，同时抑制谱系标记，而在低密度时其与DNA的结合减少。我们的结果为先前被忽视但普遍存在的密度依赖性基因调控现象提供了新的见解。
