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DUX4 activates a transcriptional network involving Krüppel-like factors KLF17 and KLF18 [KLF17_KLF18_OE]

ABSTRACT: DUX4 is a critical regulator of gene expression during human embryonic development and is the driver of facioscapulohumeral muscular dystrophy (FSHD). In this study, we demonstrate that DUX4 induces expression of Krüppel-like factor 18 (KLF18), which is necessary for the subsequent activation of KLF17 and a subset of genes induced in the DUX4 transcriptional network. Loss of KLF18 partially disrupts the DUX4 transcriptional network in both muscle cells and human embryonic stem cells, including genes associated with zygotic genome activation. KLF18 binds to the promoter regions of many of the genes it regulates but also requires DUX4 expression to transcriptionally activate many of its targets, indicating a feed-forward regulatory mechanism. While KLF17 and KLF18 have high homology in the zinc-finger DNA binding domain, human KLF18 contains a region with a variable number of tandem repeats (VNTRs) of fourteen amino acids predicted to form a beta-solenoid-like protein structure that is absent in rodent homologs and variably present in other species. Multiple structural variants consisting of different numbers and positions of repeat deletions are present in the human population, although initial studies do not show evidence of functional differences among the most common variants. These studies identify KLF18 as a key transcription factor in a feed-forward transcriptional network regulating early embryonic genes and the pathological DUX4 program in facioscapulohumeral dystrophy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299603 | GEO | 2026/06/10

REPOSITORIES: GEO

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DUX4 activates a transcriptional network involving Krüppel-like factors KLF17 and KLF18 [KLF17_KLF18_OE]

Project description:DUX4 activates a transcriptional network involving Krüppel-like factors KLF17 and KLF18 [KLF17_KLF18_OE]

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