YEATS4 Human

What is YEATS4 and what is its primary function in human cells?

YEATS4 is a highly conserved nuclear protein essential for cell viability that functions primarily as a transcriptional regulator. It is incorporated into multisubunit chromatin modification complexes, specifically the human TIP60/TRRAP and SRCAP complexes, which mediate the incorporation of variant histone proteins into nucleosomes . Unlike typical transcription factors, YEATS4 lacks a DNA-binding domain but contains a DNA-activating domain that enables it to bind to and activate other transcription factors .

YEATS4 belongs to a protein family characterized by the presence of an N-terminal YEATS domain and shares high homology with transcription factor family members AF-9 and ENL . In normal cellular physiology, YEATS4 plays crucial roles in cell cycle regulation, DNA damage repair during replication, and prevention of cellular senescence .

What cellular pathways does YEATS4 participate in?

YEATS4 participates in several critical cellular pathways:

• Cell Cycle Regulation: YEATS4 influences cell cycle progression through its inhibitory effect on p21 and subsequent repression of p53 activity .

• Senescence Regulation: Overexpression of YEATS4 abrogates senescence in human bronchial epithelial cells, while its knockdown induces cellular senescence in cancer cells .

• DNA Damage Repair: YEATS4 plays an important role in DNA repair during replication. Upregulation promotes DNA damage repair and prevents cell death, whereas downregulation inhibits DNA replication and induces apoptosis .

• Transcriptional Regulation: As a component of the TIP60/TRRAP and SRCAP complexes, YEATS4 contributes to chromatin modification and transcriptional regulation of various target genes .

• Cancer-Associated Networks: Network analysis has identified YEATS4 as being associated with protumorigenic functions through networks centered around known targets including p53, CDKN1A, and MYC .

How evolutionarily conserved is YEATS4 across species?

YEATS4 demonstrates remarkable evolutionary conservation, particularly in its N-terminal YEATS domain. The yeast homolog Yaf9 shares 80% similarity and 53% identity with human YEATS4, with most similarities concentrated in the N-terminal region . This high degree of conservation suggests the fundamental importance of YEATS4 in cellular processes.

The functional similarities between Yaf9 and YEATS4 are significant. In Saccharomyces cerevisiae, Yaf9 constitutes the histone acetyltransferase complex NuA4 and the chromatin remodeling complex SWR1 . Similarly, in mammals, YEATS4 is a subunit of the SRCAP and Tip60 complexes, which correspond to the yeast SWR1 and NuA4 complexes, respectively . This evolutionary conservation indicates that yeast models may be valuable for studying the mechanisms of YEATS4 in mammalian cells.

What are established methods for studying YEATS4 expression in experimental settings?

Several validated methodologies are employed to study YEATS4 expression:

• Quantitative PCR (qPCR): For measuring YEATS4 mRNA expression levels in cell lines and tissue samples.

• Western Blotting: For detecting YEATS4 protein expression levels and post-translational modifications.

• Immunohistochemistry (IHC): For evaluating YEATS4 expression in tissue samples. A standardized scoring system based on staining intensity can be employed:

  • Intensity score: 0 = negative, 1 = weak, 2 = moderate, 3 = strong

  • Expression categorized as high (Intensity score ≥ 2) or low (Intensity score ≤ 1)

• Gene Copy Number Analysis: Methods such as fluorescence in situ hybridization (FISH) or comparative genomic hybridization (CGH) to detect YEATS4 amplification at the DNA level.

• Integrative Genomic Analysis: Integration of copy number and gene expression data to identify concurrent DNA and expression alterations of YEATS4, as demonstrated in studies of NSCLC .

What experimental approaches effectively modulate YEATS4 function?

Several approaches have been validated for modulating YEATS4 function:

• RNA Interference (RNAi):

  • siRNA-mediated knockdown for transient YEATS4 depletion

  • shRNA-mediated knockdown for stable YEATS4 depletion

  RNAi-mediated attenuation of YEATS4 in human lung cancer cells has been shown to reduce proliferation and tumor growth, impair colony formation, and induce cellular senescence .

• Overexpression Systems:

  • Plasmid-based overexpression of YEATS4 cDNA

  • Viral vector-mediated overexpression for stable integration

  Overexpression of YEATS4 in human bronchial epithelial cells has been demonstrated to abrogate senescence .

• CRISPR/Cas9 Gene Editing:

  • For generating YEATS4 knockout cell lines

  • For introducing specific mutations or tags at the endogenous YEATS4 locus

• Small Molecule Modulation:

  • The development of small-molecule inhibitors targeting YEATS4 has been proposed as an approach for cancer therapy

  • These inhibitors could function by reducing YEATS4 expression or preventing interactions between YEATS4 and other molecules

What experimental models are appropriate for YEATS4 functional studies?

Several experimental models have demonstrated utility for YEATS4 research:

• Cell Line Models:

  • Human lung cancer cell lines with YEATS4 amplification for knockdown studies

  • Human bronchial epithelial cells for overexpression studies

  • Gastric cancer cell lines for studying YEATS4's role in gastric cancer progression

  • Bladder cancer cell lines for studying YEATS4's role in cisplatin sensitivity

• Yeast Models: Given the high conservation between yeast Yaf9 and human YEATS4, Saccharomyces cerevisiae serves as a model organism to study YEATS4 structure, function, and mechanisms .

• Xenograft Models: Mouse xenograft models have been used to study the effects of YEATS4 knockdown on tumor growth in vivo .

• Patient-Derived Samples: Analysis of YEATS4 expression in patient-derived samples provides clinically relevant insights into YEATS4's role in human cancers .

How does YEATS4 amplification contribute to cancer development?

YEATS4 amplification promotes oncogenesis through multiple mechanisms:

• Inhibition of Senescence: Overexpression of YEATS4 abrogates senescence in human bronchial epithelial cells, allowing cells to bypass this critical anti-cancer barrier .

• Promotion of Cell Proliferation: YEATS4 amplification enhances cancer cell proliferation, as evidenced by reduced proliferation following YEATS4 knockdown in cancer cell lines .

• Inhibition of p53 and p21: YEATS4 negatively regulates the p21-p53 pathway, which normally functions to suppress tumor growth .

• Enhancement of DNA Damage Repair: Upregulation of YEATS4 promotes DNA damage repair and prevents cancer cell death, contributing to cancer cell survival .

• Activation of Oncogenic Networks: YEATS4 is associated with cancer-promoting networks centered around known oncogenes such as MYC and MYCN .

What pathways does YEATS4 regulate in cancer cells?

YEATS4 regulates several key pathways in cancer cells:

Network analysis following YEATS4 knockdown identified two key networks associated with protumorigenic functions: (1) cancer and (2) cell death, survival, cell cycle, and cell morphology. These networks were centered around known targets or binding partners of YEATS4 including p53, CDKN1A, and MYC .

How does YEATS4 expression affect treatment response in cancer?

YEATS4 expression significantly impacts treatment response, particularly to chemotherapeutic agents:

• Cisplatin Sensitivity: YEATS4 expression affects cellular responses to cisplatin, with increased levels associated with resistance and decreased levels with sensitivity . Targeting the KAT8/YEATS4 axis has been reported to increase cisplatin sensitivity in bladder cancer .

• Resistance Mechanisms: The promotion of DNA damage repair by YEATS4 may contribute to therapy resistance by enhancing cancer cell survival following DNA-damaging treatments .

• Potential Therapeutic Target: Given its role in therapy resistance, YEATS4 has emerged as a potential target for cancer treatment. Inhibiting YEATS4 could potentially sensitize cancer cells to conventional chemotherapeutic agents .

• Biomarker Potential: YEATS4 expression levels could serve as a biomarker to predict treatment response, with high expression associated with poorer clinical outcomes .

What are the molecular mechanisms of YEATS4-mediated transcriptional regulation?

The molecular mechanisms of YEATS4-mediated transcriptional regulation involve several sophisticated processes:

• Chromatin Modification: As a component of the TIP60/TRRAP and SRCAP complexes, YEATS4 participates in chromatin modification, particularly the incorporation of histone variant H2A into nucleosomes .

• Transcription Factor Activation: YEATS4 contains a DNA-activating domain that binds to and activates other transcription factors, promoting the binding of these factors to DNA and enhancing target gene expression .

• p53 Pathway Regulation: YEATS4 inhibits p21, thereby repressing p53 activity under unstressed conditions .

• Interaction with Transcription Factors: YEATS4 interacts with MYC, MYCN, and potentially regulates Serum Response Factor (SRF) gene sets .

• Gene-Specific Effects: Expression profiling following YEATS4 knockdown identified 32 differentially expressed genes (27 overexpressed and 5 underexpressed) across multiple cell lines with YEATS4 amplification .

How does YEATS4 interact with chromatin remodeling complexes?

YEATS4 interacts with chromatin remodeling complexes through several mechanisms:

• Component of Multisubunit Complexes: YEATS4 is incorporated into the human TIP60/TRRAP and SRCAP complexes . These complexes are responsible for specific chromatin modifications that influence gene expression.

• Evolutionary Conservation of Complex Interactions: The yeast homolog of YEATS4, Yaf9, is a component of the NuA4 histone acetyltransferase complex and the SWR1 chromatin remodeling complex. These correspond to the mammalian Tip60 and SRCAP complexes, respectively .

• Facilitation of Complex Localization: YEATS4, like its yeast homolog Yaf9, may facilitate the localization of these complexes to the promoter regions of target genes .

• Histone Variant Incorporation: The SRCAP complex, which includes YEATS4, mediates the incorporation of histone variant H2A into nucleosomes, altering chromatin structure and affecting transcriptional regulation .

• Gene-Specific Targeting: Through its interaction with transcription factors like MYC and p53, YEATS4 may help direct chromatin remodeling complexes to specific genomic loci.

What is the role of YEATS4 in DNA damage repair?

YEATS4 plays a significant role in DNA damage repair with important implications for genome stability:

• Promotion of DNA Damage Repair: Upregulation of YEATS4 promotes DNA damage repair during replication, preventing cell death. Conversely, downregulation of YEATS4 inhibits DNA replication and induces apoptosis .

• Cell Survival Regulation: By enhancing DNA repair capacity, YEATS4 contributes to cell survival following DNA damage. This function may be particularly relevant in cancer cells, where YEATS4 amplification could promote survival despite genomic instability.

• Therapy Response Modulation: YEATS4's role in DNA repair influences cellular responses to DNA-damaging therapies such as cisplatin. Increased YEATS4 expression is associated with cisplatin resistance, while decreased expression correlates with increased sensitivity .

• Genome Stability Impact: Given its involvement in DNA repair, YEATS4 likely influences genome stability. Dysregulation of YEATS4 could potentially lead to alterations in DNA repair efficiency.

• Potential Synthetic Lethality: The DNA repair function of YEATS4 may present opportunities for synthetic lethal therapeutic approaches, particularly in cancer contexts where other DNA repair pathways are compromised.

What are potential therapeutic strategies targeting YEATS4 in cancer?

Several therapeutic strategies targeting YEATS4 in cancer are being explored:

• RNA Interference-Based Approaches: siRNA or shRNA targeting YEATS4 has shown efficacy in reducing cancer cell proliferation and tumor growth in preclinical models .

• Small Molecule Inhibitors: Development of small-molecule inhibitors targeting YEATS4 has been proposed as an attractive approach for cancer therapy . These inhibitors could:

  • Reduce or inhibit YEATS4 expression

  • Prevent interactions between YEATS4 and other molecules

  • Disrupt YEATS4's incorporation into chromatin-modifying complexes

• Combination Therapies: Targeting YEATS4 in combination with conventional chemotherapy shows promise. For example, inhibiting the KAT8/YEATS4 axis increases cisplatin sensitivity in bladder cancer .

• Targeting Downstream Effectors: Identifying and targeting critical downstream effectors of YEATS4-mediated oncogenesis could provide alternative therapeutic strategies.

• Synthetic Lethal Approaches: Exploiting synthetic lethal interactions between YEATS4 inhibition and other genetic alterations common in cancer could enable cancer-specific targeting.

How can YEATS4 serve as a biomarker in cancer?

YEATS4 shows potential as a biomarker in several aspects of cancer management:

What methodological challenges exist in developing YEATS4 inhibitors?

The development of YEATS4 inhibitors faces several methodological challenges:

• Structural Complexity: YEATS4 functions as part of multisubunit protein complexes, making it challenging to design inhibitors that specifically disrupt its activities without affecting other components.

• Lack of Enzymatic Activity: Unlike kinases or other enzymes with clear catalytic sites, YEATS4 mediates its effects through protein-protein interactions, which are traditionally more difficult to target with small molecules.

• Limited Structural Information: While some information is available about the YEATS domain, detailed structural data on the full-length YEATS4 protein and its interactions is limited, hampering structure-based drug design efforts.

• Specificity Concerns: The YEATS domain is found in several proteins, raising concerns about the specificity of inhibitors targeting this domain and potential off-target effects.

• Delivery Challenges: For RNA-based therapeutics targeting YEATS4, efficient delivery to cancer cells remains a significant challenge.