The Isl1/Ldb1 Complex Orchestrates Genome-wide Chromatin Organization to Instruct Differentiation of Multipotent Cardiac Progenitors

Cell Stem Cell
Luca CaputoGergana Dobreva

Abstract

Cardiac stem/progenitor cells hold great potential for regenerative therapies; however, the mechanisms regulating their expansion and differentiation remain insufficiently defined. Here we show that Ldb1 is a central regulator of genome organization in cardiac progenitor cells, which is crucial for cardiac lineage differentiation and heart development. We demonstrate that Ldb1 binds to the key regulator of cardiac progenitors, Isl1, and protects it from degradation. Furthermore, the Isl1/Ldb1 complex promotes long-range enhancer-promoter interactions at the loci of the core cardiac transcription factors Mef2c and Hand2. Chromosome conformation capture followed by sequencing identified specific Ldb1-mediated interactions of the Isl1/Ldb1 responsive Mef2c anterior heart field enhancer with genes that play key roles in cardiac progenitor cell function and cardiovascular development. Importantly, the expression of these genes was downregulated upon Ldb1 depletion and Isl1/Ldb1 haplodeficiency. In conclusion, the Isl1/Ldb1 complex orchestrates a network for heart-specific transcriptional regulation and coordination in three-dimensional space during cardiogenesis.

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Citations

Apr 24, 2016·Nucleic Acids Research·Yang WangChunyan Zhou
May 19, 2017·Nucleic Acids Research·Ivan Krivega, Ann Dean
Jan 21, 2017·Scientific Reports·Hagen R WitzelGergana D Dobreva
Jun 27, 2017·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Adrien NaveauOphir D Klein
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May 28, 2019·Nature Communications·Alessandro MagliRita C R Perlingeiro
Mar 16, 2017·Genesis : the Journal of Genetics and Development·Kathrin WernerPetra Pandur
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May 16, 2019·Nature Reviews. Genetics·Stefan Schoenfelder, Peter Fraser
May 23, 2018·Nature Communications·Anastasia FelkerChristian Mosimann
Apr 25, 2017·The Journal of Clinical Investigation·Xuejun YuanThomas Braun
Jan 11, 2019·Nature·Kevin MonahanStavros Lomvardas
Nov 27, 2020·Journal of Molecular and Cellular Cardiology·Alessandro Bertero, Manuel Rosa-Garrido
Dec 4, 2020·Science Advances·Konstantinos E HatzistergosJoshua M Hare
Jan 6, 2021·Nature Structural & Molecular Biology·Naoki KuboBing Ren
Feb 14, 2021·Journal of Cardiovascular Development and Disease·Cassie L KemmlerChristian Mosimann
Mar 9, 2021·Frontiers in Cardiovascular Medicine·Meihua SheQun Zeng
May 18, 2020·Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms·Hei Tung FongTakao Inoue
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Aug 13, 2021·Nature Reviews. Cardiology·Chukwuemeka G Anene-NzeluRoger S Y Foo
Jul 15, 2021·American Journal of Physiology. Cell Physiology·Si-Qiang ZhengGuo-Wei He

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