β-catenin links cell seeding density to global gene expression during mouse embryonic stem cell differentiation

Lucy LeBlanc; Mijeong Kim; Aparna Kambhampati; Albert J Son; Nereida Ramirez; Jonghwan Kim

doi:10.1016/j.isci.2021.103541

β-catenin links cell seeding density to global gene expression during mouse embryonic stem cell differentiation

iScience. 2021 Dec 1;25(1):103541. doi: 10.1016/j.isci.2021.103541. eCollection 2022 Jan 21.

Authors

Lucy LeBlanc^{1

2}, Mijeong Kim^{1

2}, Aparna Kambhampati^{1

3}, Albert J Son¹, Nereida Ramirez^{1

4}, Jonghwan Kim^{1

5}

Affiliations

¹ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
² Interdisciplinary Life Sciences Graduate Program, The University of Texas at Austin, Austin, TX 78712, USA.
³ UT Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
⁴ Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA.
⁵ Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, TX 78712, USA.

Abstract

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.

Keywords: Cell biology; Stem cells research; Transcriptomics.

Grants and funding

R01 GM112722/GM/NIGMS NIH HHS/United States