TY - JOUR
T1 - GLI transcriptional repression is inert prior to Hedgehog pathway activation
AU - Lex, Rachel K.
AU - Zhou, Weiqiang
AU - Ji, Zhicheng
AU - Falkenstein, Kristin N.
AU - Schuler, Kaleigh E.
AU - Windsor, Kathryn E.
AU - Kim, Joseph D.
AU - Ji, Hongkai
AU - Vokes, Steven A.
N1 - Funding Information:
We thank Matt Anderson and Mark Lewandoski for sharing their protocol for clearing embryos, We thank the Henikoff Lab and EpiCypher for providing CUT&Tag reagents, and Jonathan Eggenschwiler for providing the GLI2 antibody. We thank Jessica Podnar from the Genomic Sequencing and Analysis Facility at the University of Texas at Austin, Anna Webb from the Center for Biomedical Research Support at the University of Texas at Austin and Elle Roberson for technical advice, and Janani Ramachandran for comments on this manuscript. This work was supported by NIH R01HD073151 (to S.A.V. and H.J.), F31DE027597 (to R.K.L.) and R01HG009518 (to H.J.).
Funding Information:
We thank Matt Anderson and Mark Lewandoski for sharing their protocol for clearing embryos, We thank the Henikoff Lab and EpiCypher for providing CUT&Tag reagents, and Jonathan Eggenschwiler for providing the GLI2 antibody. We thank Jessica Podnar from the Genomic Sequencing and Analysis Facility at the University of Texas at Austin, Anna Webb from the Center for Biomedical Research Support at the University of Texas at Austin and Elle Roberson for technical advice, and Janani Ramachandran for comments on this manuscript. This work was supported by NIH R01HD073151 (to S.A.V. and H.J.), F31DE027597 (to R.K.L.) and R01HG009518 (to H.J.).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - The Hedgehog (HH) pathway regulates a spectrum of developmental processes through the transcriptional mediation of GLI proteins. GLI repressors control tissue patterning by preventing sub-threshold activation of HH target genes, presumably even before HH induction, while lack of GLI repression activates most targets. Despite GLI repression being central to HH regulation, it is unknown when it first becomes established in HH-responsive tissues. Here, we investigate whether GLI3 prevents precocious gene expression during limb development. Contrary to current dogma, we find that GLI3 is inert prior to HH signaling. While GLI3 binds to most targets, loss of Gli3 does not increase target gene expression, enhancer acetylation or accessibility, as it does post-HH signaling. Furthermore, GLI repression is established independently of HH signaling, but after its onset. Collectively, these surprising results challenge current GLI pre-patterning models and demonstrate that GLI repression is not a default state for the HH pathway.
AB - The Hedgehog (HH) pathway regulates a spectrum of developmental processes through the transcriptional mediation of GLI proteins. GLI repressors control tissue patterning by preventing sub-threshold activation of HH target genes, presumably even before HH induction, while lack of GLI repression activates most targets. Despite GLI repression being central to HH regulation, it is unknown when it first becomes established in HH-responsive tissues. Here, we investigate whether GLI3 prevents precocious gene expression during limb development. Contrary to current dogma, we find that GLI3 is inert prior to HH signaling. While GLI3 binds to most targets, loss of Gli3 does not increase target gene expression, enhancer acetylation or accessibility, as it does post-HH signaling. Furthermore, GLI repression is established independently of HH signaling, but after its onset. Collectively, these surprising results challenge current GLI pre-patterning models and demonstrate that GLI repression is not a default state for the HH pathway.
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U2 - 10.1038/s41467-022-28485-4
DO - 10.1038/s41467-022-28485-4
M3 - Article
C2 - 35145123
AN - SCOPUS:85124445708
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 808
ER -