Y chromosome regulates gene expression during human development: Functions beyond sex determination clarified

The Y chromosome is present only in males and is responsible for sex determination. However, because it is extremely small compared to other chromosomes and has lost a significant number of genes throughout evolution, some scientists have suggested: "It could eventually disappear in the future."

A research group including Assistant Professor Tomohiko Akiyama of the Graduate School of Medicine at Yokohama City University (currently affiliated with the Department of Systems Medicine (Sakaguchi Laboratory), Keio University School of Medicine) has revealed that the gene UTY on the Y chromosome works in coordination with its counterpart UTX on the X chromosome to play a crucial role in early human development.

While the Y chromosome has traditionally been understood as a chromosome primarily involved in sex determination and reproductive functions, this study demonstrates that UTY, which remains on the Y chromosome, works alongside UTX to support the appropriate placement of transcription factors. Through this mechanism, it regulates gene expression and controls pluripotency maintenance and differentiation processes during early development.

Furthermore, the study revealed that despite having lost almost all of its enzymatic activity over time, UTY functions via non-catalytic properties as a "scaffold" to support transcriptional regulation. This discovery reevaluates conventional perspectives on the Y chromosome and deepens the understanding of sex-based differences in development. The findings were published online in Development.

Genes typically exist as pairs on homologous chromosomes. However, UTY is an exception, residing exclusively on the Y chromosome and pairing with the homologous gene UTX on the X chromosome. While UTX is known as an enzyme that regulates gene expression (specifically, a histone H3K27-specific demethylase containing a JmjC domain), UTY has acquired mutations during evolution and lost nearly all of its enzymatic activity. Because of this and its low expression levels, its function long remained a mystery.

To clarify the role of UTY in human development, the research group conducted analyses using human embryonic stem cells (ESCs) possessing a Y chromosome. Because the Y chromosome contains numerous repetitive sequences and low gene expression levels, functional analysis has historically been considered difficult.

In this study, researchers used genome editing techniques to attach an artificial tag to UTY, allowing them to analyze its intracellular localization and genomic binding regions with high precision. The results revealed that UTY binds to approximately 10,000 locations across the genome, spanning all chromosomes, which is a far more extensive distribution than previously thought.

Upon examining the binding sites, the majority were located in promoter and enhancer regions, which are critical areas for regulating gene expression. Moreover, its binding distribution largely overlapped with that of UTX, demonstrating that UTY is involved in regulating gene expression while functionally overlapping with UTX. Furthermore, analysis of cells deficient in both UTX and UTY revealed that instead of acting directly as an enzyme, UTY plays a role in supporting gene expression by positioning transcription factors and chromatin regulators at the appropriate genomic regions.

In fact, when both UTX and UTY were deleted, the binding patterns of key transcription factors such as OCT4 and SOX2 shifted extensively, resulting in abnormal gene expression. Additionally, while deleting either UTX or UTY individually showed no major impact, a simultaneous deficiency in both rendered the cells unable to maintain an undifferentiated state.

Furthermore, when transplanted into immunodeficient mice, the cells lost their ability to differentiate into various tissues (teratoma-forming capability), confirming that pluripotency was severely impaired.

These results indicate that UTX and UTY cooperate to play an essential role in maintaining pluripotency.

This study demonstrates that the Y chromosome, which has been long thought to be "small and potentially fading away," plays an important role in controlling gene expression during human development.

In particular, the discovery that UTY, despite possessing almost no enzymatic activity, supports gene expression by adjusting the arrangement of transcription factors provides a new understanding of gene regulation.

Furthermore, it suggests the possibility of differences in transcriptional regulation between males and females. Future applications are expected to include elucidating the molecular foundation of developmental regulation based on sex differences, as well as advancing the understanding of infertility and developmental disorders.

Journal Information
Publication: Development
Title: Functional redundancy between UTY and UTX in regulating the localization of transcription factors involved in pluripotency
DOI: 10.1242/dev.205328