Membrane-Bound Transcription Factor MYRF Critically Regulates Developmental Timing by Promoting lin-4 microRNA Expression in C. elegans

Core Concepts

The membrane-bound transcription factor MYRF is an essential, cell-autonomous regulator of lin-4 microRNA expression, which is a critical determinant of developmental timing in C. elegans.

Abstract

The content explores the role of the membrane-bound transcription factor MYRF in regulating the expression of the microRNA lin-4 during C. elegans larval development. Key highlights: The nuclear accumulation of the cleaved N-terminal MYRF-1 coincides with the induction of lin-4 expression in late L1 stage. MYRF-1 is required for the activation of lin-4 transcription, as lin-4 expression is significantly reduced or absent in various myrf-1 loss-of-function mutants. MYRF-1 regulates lin-4 expression in a cell-autonomous manner, as tissue-specific rescue and ablation experiments demonstrate. Overexpression of a hyperactive MYRF-1 variant can prematurely induce lin-4 expression in embryos and early L1 larvae. The lin-4 promoter DNA can recruit and sequester MYRF-1, potentially interfering with its normal developmental functions. MYRF-1 selectively regulates the expression of a subset of microRNAs, including lin-4, during the L1-L2 transition. These findings establish MYRF-1 as a key transcriptional regulator of lin-4, which is crucial for controlling developmental timing in C. elegans.

Stats

The content includes the following key data: "lin-4 transcription is not activated in myrf-1(syb1491) and myrf-1(syb1468) mutants." "lin-4 transcription is not activated in myrf-1(ju1121) mutants, except for a few pharyngeal nuclei." "The abundance of mature lin-4 miRNAs is significantly reduced in myrf-1(ju1121) mutants compared to wild-type." "Overexpression of a hyperactive MYRF-1 variant causes premature expression of lin-4 in embryos and early L1 larvae." "A subset of animals carrying the lin-4 promoter reporter transgene (maIs134) exhibit constitutive dauer formation and developmental delay."

Quotes

"MYRF-1 is an essential, cell-autonomous driver of lin-4 expression." "Hyperactive MYRF can precociously activate endogenous lin-4 transcription." "The tandem lin-4 promoter DNA recruits MYRF-1GFP to form visible loci in the nucleus, suggesting that MYRF-1 directly binds to the lin-4 promoter."

Key Insights Distilled From

Essential Function of Transmembrane Transcription Factor MYRF in Promoting Transcription of miRNA lin-4 during C. elegans Development

by Xu,Z., Wang,... at www.biorxiv.org 06-24-2023

https://www.biorxiv.org/content/10.1101/2023.06.22.546200v3

Deeper Inquiries

How do the developmental signals that control MYRF-1 cleavage and nuclear translocation integrate with the regulation of lin-4 expression?

The developmental signals that control MYRF-1 cleavage and nuclear translocation play a crucial role in the regulation of lin-4 expression. MYRF-1 is initially localized on the cell membrane during early L1 stages, and its cleavage and subsequent nuclear translocation coincide with the activation of lin-4 expression towards late L1. This temporal coordination suggests a direct link between MYRF-1 processing and the induction of lin-4 transcription. The increased nuclear accumulation of N-MYRF-1 during late L1 aligns with the upregulation of lin-4 expression, indicating that MYRF-1 acts as a key regulator of lin-4 activation. The precise timing of MYRF-1 cleavage and nuclear translocation likely integrates with the developmental signals that trigger lin-4 expression, highlighting the intricate regulatory network governing developmental timing in C. elegans.

What are the other key transcriptional targets of MYRF-1 besides lin-4, and how do they contribute to the overall regulation of developmental timing in C. elegans?

In addition to lin-4, MYRF-1 regulates a selective subset of microRNAs during the L1-L2 transition in C. elegans. Through miRNA sequencing analysis, several differentially expressed miRNAs have been identified in myrf-1 mutants, indicating that MYRF-1 has broader transcriptional targets beyond lin-4. These miRNAs are hierarchically clustered and show distinct expression patterns in myrf-1 mutants compared to wild-type animals. The phylogenetic analysis of these differentially expressed miRNAs reveals unique relationships among the miRNA genes, suggesting that MYRF-1 regulates a diverse set of transcriptional targets involved in developmental timing. The expression of transcriptional reporters, such as Pmir-48-gfp, Pmir-73-gfp, and Pmir-230-gfp, further supports the role of MYRF-1 in regulating a specific subset of microRNAs during the L1-L2 transition. These transcriptional targets likely contribute to the overall regulation of developmental timing in C. elegans by fine-tuning gene expression patterns and coordinating the progression of developmental stages. By modulating the expression of these key transcriptional targets, MYRF-1 plays a critical role in orchestrating the intricate processes underlying developmental timing in C. elegans.

Given the selective regulation of microRNA expression by MYRF-1, what are the broader implications of this transcription factor in coordinating post-transcriptional gene regulation during animal development?

The selective regulation of microRNA expression by MYRF-1 has significant implications for coordinating post-transcriptional gene regulation during animal development. MicroRNAs play a crucial role in fine-tuning gene expression by targeting specific mRNAs for degradation or translational repression. By regulating a selective subset of microRNAs, MYRF-1 can modulate the expression of key genes involved in various developmental processes, including cell differentiation, tissue morphogenesis, and temporal patterning. The broader implications of MYRF-1's role in coordinating post-transcriptional gene regulation extend to the precise control of developmental timing and the maintenance of cellular homeostasis. By modulating the expression of microRNAs, MYRF-1 can influence the timing of key developmental events, such as cell division, differentiation, and maturation. This regulatory mechanism ensures the proper progression of developmental stages and the establishment of functional tissues and organs in the organism. Overall, MYRF-1's selective regulation of microRNA expression underscores its importance in orchestrating post-transcriptional gene regulation during animal development. By fine-tuning gene expression patterns through the modulation of microRNAs, MYRF-1 contributes to the intricate regulatory network that governs the precise timing and coordination of developmental processes in C. elegans.