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
Affiliations
Jerome Jatzlau
Institute of Chemistry and Biochemistry - Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies (BSRT), 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
Paul-Lennard Mendez
Institute of Chemistry and Biochemistry - Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; International Max-Planck Research School for Biology AND Computation (IMPRS-BAC), 14195 Berlin, Germany
Aybuge Altay
Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
Lion Raaz
Institute of Chemistry and Biochemistry - Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; International Max-Planck Research School for Biology AND Computation (IMPRS-BAC), 14195 Berlin, Germany; Institute of Medical and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany
Yufei Zhang
Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
Sophia Mähr
Institute of Chemistry and Biochemistry - Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
Akin Sesver
Institute of Chemistry and Biochemistry - Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
Maria Reichenbach
Institute of Chemistry and Biochemistry - Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
Stefan Mundlos
Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; International Max-Planck Research School for Biology AND Computation (IMPRS-BAC), 14195 Berlin, Germany; Institute of Medical and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany
Martin Vingron
Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; International Max-Planck Research School for Biology AND Computation (IMPRS-BAC), 14195 Berlin, Germany
Petra Knaus
Institute of Chemistry and Biochemistry - Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies (BSRT), 13353 Berlin, Germany; International Max-Planck Research School for Biology AND Computation (IMPRS-BAC), 14195 Berlin, Germany; Corresponding author
Summary: 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.
