ZMYND8 is a gene that has garnered significant attention due to its multifaceted involvement in cellular processes. It encodes a protein influencing how cells maintain genetic material and regulate gene activity. Understanding its normal roles provides insight into how disruptions contribute to various health conditions. Ongoing research aims to unravel its intricate mechanisms, shedding light on potential avenues for medical advancements.
What is ZMYND8
ZMYND8, or zinc finger MYND-type containing 8, is a gene located on human chromosome 20 at band 20q13.12. It provides instructions for building the ZMYND8 protein, also known as RACK7 or PRKCBP1. This protein is found in various parts of a cell, including the cytoplasm, dendritic shafts, dendritic spines, and the nucleus.
The ZMYND8 protein has structural features that enable its functions. It contains a bromodomain and two zinc finger motifs, allowing it to interact with other molecules, particularly histones. These elements are key to its role as a transcriptional regulator, influencing the activity of other genes. Multiple versions of the ZMYND8 protein, called isoforms, can be produced from the gene through different transcript variants.
The Normal Functions of ZMYND8
The ZMYND8 protein plays a role in several cellular activities, acting as an epigenetic “reader” that interprets modifications on histone proteins. Histones are proteins around which DNA is wound, forming chromatin. Chemical tags on these histones influence gene accessibility and activity. ZMYND8 specifically recognizes certain combinations of histone modifications, such as those on histone H3 and H4.
ZMYND8 is involved in DNA repair, particularly at sites of DNA damage. When DNA strands break, ZMYND8 is recruited to these damaged regions. It recognizes histone modifications on the surrounding chromatin and recruits the NuRD complex (Nucleosome Remodeling and Histone Deacetylation). This helps silence gene activity in the damaged area, allowing for proper DNA repair through a process called homologous recombination.
Beyond DNA repair, ZMYND8 also influences gene expression, acting as both a corepressor and an activator of transcription. As a corepressor, it binds to specific histone marks and can suppress the expression of certain genes, including those linked to metastasis. Conversely, ZMYND8 can promote transcription by associating with the P-TEFb complex, which helps RNA polymerase II synthesize RNA. This dual regulatory capacity allows ZMYND8 to fine-tune gene activity across various cellular processes, including promoting neuronal differentiation.
ZMYND8’s Role in Disease
Malfunctions or altered expression of the ZMYND8 gene and its protein are linked to the development and progression of various diseases, particularly certain cancers and neurodevelopmental disorders. In cancer, ZMYND8’s role can appear contradictory, acting as both a tumor suppressor and a pro-oncogenic factor depending on the cancer type. For instance, increased ZMYND8 expression is observed in breast, prostate, colorectal, and cervical cancers, where it promotes tumor growth and angiogenesis. In breast cancer, ZMYND8 can enhance the transcription of genes that drive cell proliferation, migration, and metastasis by interacting with certain factors.
Conversely, ZMYND8 can also act as a tumor suppressor in some contexts, such as in breast, prostate, and nasopharyngeal cancers. Studies show ZMYND8 can inhibit tumor growth by promoting cell differentiation, reducing cell proliferation, and suppressing invasiveness and metastasis. For example, in breast cancer cells, ZMYND8 can inhibit cancer cell invasion by regulating epithelial genes. In acute myeloid leukemia (AML), ZMYND8 activates transcription of genes like IRF8 and MYC, which are dependencies for AML proliferation.
In addition to cancer, de novo variants in the ZMYND8 gene are associated with neurodevelopmental disorders. Individuals with these genetic changes may present with a syndrome characterized by intellectual disability, and sometimes include cardiovascular, ophthalmologic, and skeletal anomalies. Some individuals have also been diagnosed with autism spectrum disorder or show autistic features. Such variants can disrupt ZMYND8’s normal protein interactions, leading to its dysfunction in brain development.
Investigating ZMYND8
Scientists employ a variety of methods to investigate ZMYND8, aiming to understand its intricate mechanisms and disease associations. Genetic sequencing identifies variations or mutations within the ZMYND8 gene that contribute to disease. By comparing sequences from healthy individuals and those with disorders, scientists pinpoint specific genetic changes linked to conditions like neurodevelopmental syndromes or various cancers.
Cell culture studies are widely used to examine ZMYND8’s function at a cellular level. Researchers grow human or animal cells in controlled laboratory environments to manipulate ZMYND8 expression, either increasing or decreasing it, and then observe effects on cellular processes like DNA repair, gene expression, cell proliferation, and migration. This approach directly studies ZMYND8’s impact on cell behavior and molecular pathways.
Animal models, particularly mice and zebrafish, offer platforms for studying ZMYND8 in a whole-organism context. By introducing or removing the ZMYND8 gene, scientists observe its effects on development, disease progression, and physiology. For instance, mouse xenograft models have been used to assess the impact of ZMYND8 on tumor growth and metastasis in vivo. These research efforts are important for developing new diagnostic tools and therapeutic strategies that target ZMYND8, potentially leading to improved treatments for associated diseases.