YY1 Human

What is the molecular structure of YY1 and how does it bind to DNA?

YY1 is a ubiquitously expressed transcription factor containing four C2H2-type zinc fingers in its C-terminal domain that enable DNA binding to a consensus sequence (5′-CCGCCATNTT-3′) . The protein contains distinct functional domains: an N-terminal transcriptional activation domain, central regions involved in protein-protein interactions, and C-terminal zinc fingers that partially overlap with sequences involved in transcriptional repression . YY1 homodimers are stabilized by low-specificity RNA binding, enhancing their stability on target sequences . The protein's REPO domain interacts with polycomb group proteins and other cofactors, while its histidine tract (eleven consecutive histidine residues) promotes YY1 accumulation in nuclear speckles involved in RNA metabolism .

How does YY1 exert both transcriptional activation and repression functions?

YY1's dual functionality depends on multiple mechanisms:

• Structural basis: The N-terminal region contains a transcriptional activator domain, while sequences overlapping with the zinc fingers mediate transcriptional repression .

• Post-translational modifications: Acetylation of YY1's C-terminal domain reduces DNA-binding capacity, potentially shifting its function .

• Cofactor recruitment: The REPO domain recruits polycomb group proteins as repressive cofactors, while other domains interact with activating factors .

• Chromatin context: YY1 binds enhancers and promoters differently depending on the chromatin environment .

• RNA interactions: YY1 can bind RNA in addition to DNA, creating context-dependent regulation mechanisms as demonstrated in HTLV-1 infection where RNA binding promotes viral activation rather than the expected repression .

How does YY1 contribute to viral pathogenesis in HTLV-1 infection?

Contrary to YY1's previously documented role in transcriptional silencing of retroviruses, research has revealed that YY1 functions as a potent activator of Human T-lymphotropic virus type 1 (HTLV-1) expression . This occurs through an unexpected mechanism:

• YY1 binds to the R region of HTLV-1 RNA rather than the classical DNA-binding sites in the viral long terminal repeat (LTR) .

• This RNA-binding activity leads to increased transcription initiation and elongation of viral genes .

• YY1 overexpression profoundly activates HTLV-1 expression, while YY1 downregulation reduces it .

• The HTLV-1 R sequence alone is sufficient to provide YY1 responsiveness to a non-responsive promoter, but only in the sense orientation and only when included as part of the mRNA .

This mechanism represents a novel paradigm where a host transcription factor promotes viral replication through RNA binding rather than conventional DNA-transcription factor interaction, ultimately contributing to HTLV-1's ability to transform CD4+ T cells and lead to adult T cell leukemia/lymphoma .

What is YY1's role in diabetes pathogenesis and β-cell function?

YY1 serves as a critical regulator in β-cell maintenance and function through multiple mechanisms:

• Expression patterns: YY1 expression is suppressed in β-cells of diabetic db/db mice, mice fed high-fat diets, and human donors with Type 2 diabetes (reduced by approximately 40% in human T2D β-cells) .

• Genomic regulation: ChIP-seq in human β-cell lines revealed YY1 binds to genes involved in DNA repair pathways and cell cycle checkpoints .

• Genetic models: Disruption of YY1 specifically in β-cells leads to diabetes early in life (2-3 weeks of age) due to severe β-cell loss, characterized by:

  • 50% reduction in β-cell area at 2 weeks

  • 75% reduction in β-cell area at 3 weeks

  • Progressive hyperglycemia and reduced insulin levels

• Molecular pathways: YY1 and its target gene Ccna2 are downregulated in islets from insulin-resistant db/db mice before severe hyperglycemia develops, impairing β-cell adaptation to metabolic stress .

These findings position YY1 as a key factor linking metabolic stress to diabetes progression through dysregulation of DNA repair and cell cycle control in β-cells .

What evidence connects YY1 to cancer progression, particularly in prostate cancer?

YY1 expression is significantly upregulated in human prostate cancer cell lines and tissues compared to normal controls . This dysregulated transcription factor functions as:

• A promoter of tumor progression: YY1 overexpression correlates with advancing disease stages in prostate cancer .

• A regulator of drug resistance: YY1 contributes to therapeutic resistance mechanisms in cancer cells .

• An EMT facilitator: YY1 promotes epithelial-mesenchymal transition, a critical process for cancer cell invasion and metastasis .

Bioinformatic analyses of gene RNA array datasets comparing YY1 expression in prostate tumor versus normal tissues support its role in cancer pathogenesis, though variations in expression levels have been reported by different investigators . The consistent correlation between YY1 overexpression and cancer progression suggests its potential utility both as a biomarker for patient stratification and as a therapeutic target .

How does YY1 dysfunction contribute to neurodevelopmental disorders?

YY1 haploinsufficiency causes Gabriele-de Vries syndrome (OMIM #617557), a neurodevelopmental disorder characterized by psychomotor delay, intellectual disability, craniofacial dysmorphisms, intrauterine growth restriction, and behavioral alterations . This clinical presentation underscores YY1's crucial role in neuronal development and brain homeostasis:

• In mice, homozygous YY1 knockout is lethal during peri-implantation, while heterozygous mutations cause growth retardation and neurulation defects .

• YY1 regulates neurogenesis and maintains homeostasis in the developing brain .

• YY1 functions in cellular processes critical for central nervous system development, including proliferation, apoptosis, and chromatin organization .

The syndrome demonstrates how partial loss of YY1 function profoundly impacts neurodevelopment, with implications for understanding broader mechanisms of intellectual disability and developmental disorders .

What experimental approaches are most effective for investigating YY1 binding sites across the genome?

To comprehensively map YY1 binding sites, researchers employ several complementary techniques:

• Chromatin Immunoprecipitation followed by sequencing (ChIP-seq):

  • Using anti-YY1 antibodies to immunoprecipitate chromatin fragments

  • De novo motif analysis to identify enriched sequences (e.g., the AAnATGGC motif found in 80% of binding regions in human β-cell lines)

  • Bioinformatic analysis to associate binding sites with gene regulatory elements

• Pathway enrichment analysis of ChIP-seq data:

  • Reveals YY1-regulated biological processes (e.g., sister chromatid cohesion, DNA repair)

  • Quantifies enrichment (5-6 fold enrichment for chromatin cohesion pathways, 2-3 fold for DNA damage recognition)

  • Identifies direct YY1 target genes for functional validation

• Integrative genomic analysis:

  • Correlation of YY1 binding with gene expression datasets (e.g., RNA-seq)

  • Comparing binding patterns across different cell types and conditions

  • Identifying differentially regulated genes (e.g., Ccna2, a YY1 target downregulated in diabetic islets)

• Genetic manipulation approaches:

  • Creating cell- or tissue-specific YY1 knockout models

  • Measuring chromatin accessibility changes upon YY1 deletion

  • Assessing transcriptional consequences of YY1 binding site mutations

These methodologies collectively provide a comprehensive picture of YY1's genomic distribution and regulatory impact .

How can researchers effectively study YY1-mediated RNA binding versus DNA binding?

Distinguishing between YY1's RNA binding and DNA binding activities requires specialized approaches:

• Comparative binding studies:

  • RNA immunoprecipitation (RIP) versus ChIP to differentiate RNA from DNA targets

  • CLIP-seq (cross-linking immunoprecipitation-sequencing) to map RNA binding sites at nucleotide resolution

  • In vitro binding assays with purified YY1 protein and labeled RNA or DNA probes

• Functional validation strategies:

  • Utilizing the HTLV-1 R region as a model system:

    • Testing if the sequence alone provides YY1 responsiveness to a non-responsive promoter

    • Confirming orientation dependence (functions only in sense orientation)

    • Verifying it only works when included as part of the mRNA

  • Mutational analysis of putative binding sites to disrupt YY1 binding selectively to RNA or DNA

• Structural biological approaches:

  • Analyzing how YY1's zinc finger domains can accommodate both DNA and RNA binding

  • Identifying specific amino acid residues that differentiate between nucleic acid types

  • Examining how post-translational modifications might affect substrate preference

• Transcriptional readout experiments:

  • Measuring how YY1 binding to RNA affects transcription initiation and elongation

  • Comparing the effects of mutations that selectively disrupt RNA versus DNA binding

  • Analyzing recruitment of different cofactors depending on RNA or DNA binding

These methodologies collectively enable researchers to dissect YY1's unconventional dual role as both a DNA-binding transcription factor and an RNA-binding regulator .

How does YY1 contribute to three-dimensional chromatin organization?

YY1 plays sophisticated roles in 3D chromatin architecture through several mechanisms:

• Structural protein interactions:

  • YY1's REPO domain directly interacts with cohesin and condensin, key factors in chromosome organization

  • These interactions facilitate chromatin looping and establishment of topologically associating domains (TADs)

• Enhancer-promoter communication:

  • YY1 can bind simultaneously to enhancers and promoters

  • This creates functional bridges that bring distal regulatory elements into physical proximity

  • YY1 binding motifs are enriched in both enhancers and promoters

• Chromatin boundary functions:

  • YY1 binding sites are often found at domain boundaries

  • Its interaction with both activating and repressive chromatin modifiers helps establish these boundaries

  • The cohesin complex, which interacts with YY1, is essential for DNA repair by homologous recombination and maintaining DNA integrity in postmitotic cells

• DNA damage response coordination:

  • YY1 binding regions show 5-6 fold enrichment for sister chromatid cohesion pathways

  • 2-3 fold enrichment for DNA damage recognition in nucleotide excision repair

  • Enrichment for ATM-mediated double-stranded breaks repair and G1/S DNA damage checkpoint pathways

These multiple roles in chromatin architecture help explain how YY1 can exert both activating and repressive effects on gene expression in a context-dependent manner, with implications for both development and disease processes .

What is known about YY1's role in RNA processing beyond transcriptional regulation?

Beyond its classical function as a transcription factor, YY1 plays significant roles in RNA metabolism:

• Pre-mRNA splicing activities:

  • YY1 binds intronic enhancer motifs to simultaneously activate gene expression and promote splicing

  • This creates coordinated regulation of both transcription and RNA processing

• Nuclear compartmentalization:

  • The histidine tract (eleven consecutive histidine residues) promotes YY1 accumulation in nuclear speckles

  • These nuclear bodies are centers for RNA metabolism and splicing factor organization

  • This localization facilitates YY1's interaction with RNA processing machinery

• RNA-dependent dimerization:

  • YY1 homodimers are stabilized by low-specificity RNA binding

  • This RNA binding activity may directly influence molecular assemblies involved in RNA processing

• Viral RNA interactions:

  • YY1 binds to the R region of HTLV-1 RNA, affecting viral gene expression

  • This binding occurs within the context of the viral mRNA rather than DNA

  • The RNA binding promotes rather than represses viral gene expression, contrary to YY1's typical effect on retroviral DNA

These diverse RNA-related functions expand our understanding of YY1 beyond traditional transcription factor roles, highlighting its involvement in multiple layers of gene expression regulation .

What therapeutic approaches targeting YY1 show promise for cancer treatment?

Based on YY1's role in cancer progression, several therapeutic strategies are being explored:

• Direct YY1 inhibition strategies:

  • Small molecule inhibitors targeting YY1's DNA-binding zinc finger domains

  • RNA interference approaches to reduce YY1 expression levels in tumor cells

  • Disruption of specific YY1-cofactor interactions that promote cancer progression

• YY1 as a biomarker for patient stratification:

  • Using YY1 expression levels to identify patients likely to benefit from specific therapies

  • Developing YY1-based companion diagnostics for treatment selection

  • Monitoring YY1 activity as a marker of treatment response

• Targeting YY1-dependent mechanisms:

  • Inhibiting YY1's role in promoting drug resistance

  • Developing compounds that reverse YY1-mediated epithelial-mesenchymal transition

  • Focusing on prostate cancer where YY1 upregulation has been well-documented

How might understanding YY1's role in diabetes inform new treatment strategies?

YY1's critical function in β-cell maintenance and DNA repair suggests several therapeutic avenues:

• YY1 preservation strategies:

  • Developing compounds that prevent YY1 downregulation in β-cells under metabolic stress

  • Targeted approaches to maintain nuclear YY1 levels specifically in β-cells

  • Interventions addressing the 40% reduction in YY1+ β-cells observed in human T2D patients

• DNA repair pathway enhancement:

  • Targeting downstream effectors of YY1 involved in DNA repair to preserve β-cell function

  • Compensating for reduced YY1 activity in DNA damage response pathways

  • Focusing on the cohesin complex and other YY1-dependent DNA repair mechanisms

• Cell cycle regulation approaches:

  • Modulating YY1-dependent cell cycle checkpoints to enhance β-cell adaptation

  • Targeting specific YY1-regulated genes like Ccna2 to improve β-cell response to insulin resistance

  • Preventing the β-cell loss observed in YY1-deficient models (50-75% reduction in β-cell area)

• Diagnostic applications:

  • Developing methods to assess β-cell YY1 levels as a predictive biomarker for diabetes risk

  • Using YY1 pathway activity as an indicator of β-cell health and potential therapeutic efficacy

These approaches represent promising directions for novel diabetes prevention and treatment strategies focused on preserving β-cell mass and function through YY1-dependent mechanisms .