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Differential transactivation of the upstream aggrecan enhancer regulated by PAX1/9 depends on SOX9-driven transactivation
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Differential transactivation of the upstream aggrecan enhancer regulated by PAX1/9 depends on SOX9-driven transactivation
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Journal Article
Differential transactivation of the upstream aggrecan enhancer regulated by PAX1/9 depends on SOX9-driven transactivation
2019
Overview
A previously identified enhancer 10 kb upstream of the
Aggrecan
(
Acan
) gene (
UE
) can drive cartilage specific reporter expression
in vivo
. Here, we report that the paralogous transcription factors PAX1 and PAX9 differentially drive
UE
, depending on the presence or absence of SOX9-driven transactivation. In the developing vertebral column, PAX1/9 expression was inversely correlated with
Acan
expression. Moreover, PAX1/9 was co-expressed with SOX9/5/6 in the intervertebral mesenchyme and the inner annulus fibrosus (AF), and with SOX9 in the outer AF. Significant
Acan
upregulation was observed during chondrification of
Pax1
-silenced AF cells, while,
Acan
was significantly downregulated by persistent expression of
Pax1
in cartilage. Deletion of
UE
using CRISPR/Cas9 resulted in ~30% and ~40% reduction of
Acan
expression in cartilage and the AF, respectively. In the
UE
, PAX1/9 acts as weak transactivators through a PAX1/9-binding site partially overlapped with a SOX9-binding site. In the presence of SOX9, which otherwise drives robust
Acan
expression along with SOX5/6, PAX1/9 competes with SOX9 for occupancy of the binding site, resulting in reduced transactivation of
Acan
. Coimmunoprecipitation revealed the physical interaction of Pax1 with SOX9. Thus, transactivation of the
UE
is differentially regulated by concerted action of PAX1/9, SOX9, and SOX5/6 in a context-dependent manner.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/106
/ 38
/ 38/1
/ 42
/ 42/41
/ 45
/ 45/15
/ 64
/ 64/60
/ Aggrecan
/ Animals
/ CRISPR
/ Fluorescent Antibody Technique
/ Gene Expression Regulation, Developmental
/ Humanities and Social Sciences
/ Mice
/ Paired Box Transcription Factors - chemistry
/ Paired Box Transcription Factors - genetics
/ Paired Box Transcription Factors - metabolism
/ Science
