Maintenance of cell fates and regulation of the histone variant H3.3 by TLK kinase in Caenorhabditis elegans.

Yukimasa Shibata,Kiyoji Nishiwaki,Yoshiyuki Seki

doi:10.1242/bio.038448

Abstract

ABSTRACTCell-fate maintenance is important to preserve the variety of cell types that are essential for the formation and function of tissues. We previously showed that the acetylated histone-binding protein BET-1 maintains cell fate by recruiting the histone variant H2A.z. Here, we report that Caenorhabditis elegans TLK-1 and the histone H3 chaperone CAF1 prevent the accumulation of histone variant H3.3. In addition, TLK-1 and CAF1 maintain cell fate by repressing ectopic expression of transcription factors that induce cell-fate specification. Genetic analyses suggested that TLK-1 and BET-1 act in parallel pathways. In tlk-1 mutants, the loss of SIN-3, which promotes histone acetylation, suppressed a defect in cell-fate maintenance in a manner dependent on MYST family histone acetyltransferase MYS-2 and BET-1. sin-3 mutation also suppressed abnormal H3.3 incorporation. Thus, we propose a hypothesis that the regulation and interaction of histone variants play crucial roles in cell-fate maintenance through the regulation of selector genes.

Highlights

Defects in cell-fate maintenance cause aberrant cell-fate transformation, which can induce tumor formation and tissue malfunction
Isolation of tlk-1 mutants by screening for cell-fate maintenance-defective mutants We previously showed that, in C. elegans, malfunction of the machinery that maintains cell fate induces the production of extra distal tip cells (DTCs) (Shibata et al, 2010)
To identify additional genes that are required for the maintenance of cell fate, we screened for mutants that have extra DTCs and isolated two mutants of tlk-1 (Fig. 1A–D; Fig. S1A). tlk-1 encodes a serine/threonine kinase that is a member of the Tousled-like kinases (TLKs)

Summary

Introduction

Defects in cell-fate maintenance cause aberrant cell-fate transformation, which can induce tumor formation and tissue malfunction. Aberrant activation of genes that induce specific cell fates causes abnormal cell-fate transformation (Riddle et al, 2013; Halder et al, 1995; Tursun et al, 2011). The repression of the genes that specify cell fate is critical for maintaining individual cell fate. Epigenetic marks including histone modifications play important roles in transcriptional repression during development. The roles of histone variants in transcriptional repression are poorly understood. We previously showed that a histone H2A variant, H2A.z, is required to maintain cell fate in multiple cell lineages in Caenorhabditis elegans (Shibata et al, 2014).

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