人类转录调控疾病中疾病相关的 c-MYC 下调.

Cornelia de Lange syndrome (镉LS) is a rare multiorgan developmental
disorder caused by pathogenic variants in cohesin genes. It is a
genetically and clinically heterogeneous dominant (both autosomal and
X-linked) rare disease. Increasing experimental evidence indicates that
CdLS is caused by a combination of factors, such as gene expression
dysregulation, accumulation of cellular damage and cellular aging, which
collectively contribute to the CdLS phenotype. The CdLS phenotype overlaps
with a number of related diagnoses such as KBG syndrome and
Rubinstein-Taybi syndrome both caused by variants in chromatin-associated
factors other than cohesin. The molecular basis underlying these
overlapping phenotypes is not clearly defined. 这里, we found that cells
from individuals with CdLS and CdLS-related diagnoses are characterized by
global transcription disturbance and share common dysregulated pathways.
Intriguingly, c-MYC (subsequently referred to as MYC) is downregulated in
all cell lines and represents a convergent hub lying at the center of
dysregulated pathways. Subsequent treatment with estradiol restores MYC
expression by modulating cohesin occupancy at its promoter region. 在
添加, MYC activation leads to modification in expression in hundreds of
genes, which in turn reduce the oxidative stress level and genome
instability. 一起, these results show that MYC plays a pivotal role in
the etiopathogenesis of CdLS and CdLS-related diagnoses and represents a
potential therapeutic target for these conditions.