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Results for “YY1 Transcription Factor”

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PubMed2024

Targeting the transcription factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C.

An understanding of the enzymatic and scaffolding functions of epigenetic modifiers is important for the development of epigenetic therapies for cancer. The H3K4me2/3 histone demethylase KDM5C has been shown to regulate transcription. The diverse roles of KDM5C are likely determined by its interacting partners, which are still largely unknown. In this study, we screen for KDM5C-binding proteins and show that YY1 interacts with KDM5C. A synergistic antitumor effect is exerted when both KDM5C and YY1 are depleted, and targeting YY1 appears to be a vulnerability in KDM5C-deficient cancer cells. Mechanistically, KDM5C promotes global YY1 chromatin recruitment, especially at promoters. Moreover, an intact KDM5C JmjC domain but not KDM5C histone demethylase activity is required for KDM5C-mediated YY1 chromatin binding. Transcriptional profiling reveals that dual inhibition of KDM5C and YY1 increases transcriptional repression of cell cycle- and apoptosis-related genes. In summary, our work demonstrates a synthetic lethal interaction between YY1 and KDM5C and suggests combination therapies for cancer treatments.

YY1 Transcription Factor↗

PubMed2024

The L27 domain of MPP7 enhances TAZ-YY1 cooperation to renew muscle stem cells.

Stem cells regenerate differentiated cells to maintain and repair tissues and organs. They also replenish themselves, i.e. self-renew, to support a lifetime of regenerative capacity. Here we study the renewal of skeletal muscle stem cell (MuSC) during regeneration. The transcriptional co-factors TAZ/YAP (via the TEAD transcription factors) regulate cell cycle and growth while the transcription factor YY1 regulates metabolic programs for MuSC activation. We show that MPP7 and AMOT join TAZ and YY1 to regulate a selected number of common genes that harbor TEAD and YY1 binding sites. Among these common genes, Carm1 can direct MuSC renewal. We demonstrate that the L27 domain of MPP7 enhances the interaction as well as the transcriptional activity of TAZ and YY1, while AMOT acts as an intermediate to bridge them together. Furthermore, MPP7, TAZ and YY1 co-occupy the promoters of Carm1 and other common downstream genes. Our results define a renewal program comprised of two progenitor transcriptional programs, in which selected key genes are regulated by protein-protein interactions, dependent on promoter context.

YY1 Transcription Factor↗

PubMed2026

Oriented binding of transcription factors to nucleosomes remodels chromatin at human promoters.

Transcription factors (TFs) can access nucleosomes via five distinct modes: gyre-spanning, periodic-binding, dyad-binding, and end-binding modes as well as an oriented binding mode, where the TF binding motif shows orientational preference relative to the nucleosome. Here, we report the first structure of an oriented TF:nucleosome complex, where two ELF2 proteins bind to a double motif located at superhelical location +4, unwinding four helical turns of DNA from the nucleosome. We further show that unlike previously described pioneer factors, ELF2 is able to occupy all of its unmethylated, high-affinity double motifs in vivo. Motifs of ELF2 and another oriented nucleosome binder, YY1, are highly enriched downstream of transcription start sites (TSSs) of highly expressed genes, with the motifs oriented in such a way that the TSS becomes accessible upon TF binding. Our results suggest that oriented binding may be generally important for high transcriptional activity.

Nucleosomes↗

PubMed2026

LINE-1 repeats are a defining feature of the Xce.

During early development, female mammals inactivate one X chromosome to balance their X-linked gene dosage with males. While allelic choice is random in inbred mouse populations, choice can be significantly skewed in interstrain hybrids. The genetic basis of skewing has long been attributed to the mysterious "X chromosome controlling element(s)" (Xce) with different strengths among species, subspecies, and strains. When two X-chromosomes with different Xce strengths are inherited by offspring, the X chromosome with the stronger Xce will have a higher probability of remaining active. Here, we provide evidence that L1Tf repeats-a subfamily of long interspersed nuclear elements 1-plays a role in determining Xce strength. L1Tf elements form a condensed core within the inactive X (Xi) territory. Mouse strains with varying Xce strengths differ in the L1Tf copy number on the X chromosome, with the strength of the Xce allele being inversely related to L1Tf copy number. L1Tf expression mediates the Xce effect. However, in contrast to a prior report, L1Tf RNA does not coat the Xi. Rather, L1Tf promotes condensation of the Xi core. Intriguingly, L1Tfs recruit and sequester YY1 from active genes, accelerating XCI in cis. Thus, L1Tf copy number, expression, and binding of YY1 are key defining features of the Xce. We propose a model in which the Xce influences the choice of Xist alleles by promoting YY1 binding to the nucleation site for the initiation of Xist spreading.

Animals↗