Fluid shear stress-modulated chromatin accessibility reveals the mechano-dependency of endothelial SMAD1/5-mediated gene transcription

Jerome Jatzlau; Paul-Lennard Mendez; Aybuge Altay; Lion Raaz; Yufei Zhang; Sophia Mähr; Akin Sesver; Maria Reichenbach; Stefan Mundlos; Martin Vingron; Petra Knaus

doi:10.1016/j.isci.2023.107405

Fluid shear stress-modulated chromatin accessibility reveals the mechano-dependency of endothelial SMAD1/5-mediated gene transcription

iScience. 2023 Jul 17;26(9):107405. doi: 10.1016/j.isci.2023.107405. eCollection 2023 Sep 15.

Authors

Jerome Jatzlau^{1

2

3}, Paul-Lennard Mendez^{1

3

4}, Aybuge Altay³, Lion Raaz^{1

3

4

5}, Yufei Zhang³, Sophia Mähr¹, Akin Sesver¹, Maria Reichenbach¹, Stefan Mundlos^{3

4

5}, Martin Vingron^{3

4}, Petra Knaus^{1

2

4}

Affiliations

¹ Institute of Chemistry and Biochemistry - Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
² Berlin-Brandenburg School for Regenerative Therapies (BSRT), 13353 Berlin, Germany.
³ Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
⁴ International Max-Planck Research School for Biology AND Computation (IMPRS-BAC), 14195 Berlin, Germany.
⁵ Institute of Medical and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany.

Abstract

Bone morphogenetic protein (BMP) signaling and fluid shear stress (FSS) mediate complementary functions in vascular homeostasis and disease development. It remains to be shown whether altered chromatin accessibility downstream of BMP and FSS offers a crosstalk level to explain changes in SMAD-dependent transcription. Here, we employed ATAC-seq to analyze arterial endothelial cells stimulated with BMP9 and/or FSS. We found that BMP9-sensitive regions harbor non-palindromic GC-rich SMAD-binding elements (GGCTCC) and 69.7% of these regions become BMP-insensitive in the presence of FSS. While GATA and KLF transcription factor (TF) motifs are unique to BMP9- and FSS-sensitive regions, respectively, SOX motifs are common to both. Finally, we show that both SOX(13/18) and GATA(2/3/6) family members are directly upregulated by SMAD1/5. These findings highlight the mechano-dependency of SMAD-signaling by a sequential mechanism of first elevated pioneer TF expression, allowing subsequent chromatin opening to eventually providing accessibility to novel SMAD binding sites.

Keywords: Biological sciences; Molecular biology; Molecular interaction.