A C. elegans LSD1 Demethylase Contributes to Germline Immortality by Reprogramming Epigenetic Memory

Abstract

Recently it has been proposed that di-methylation of histone H3 on lysine 4 (H3K4me2) acts as an epigenetic memory to maintain transcriptional patterns in developing tissues. This model suggests that there may be a requirement to reprogram this modification in the germline to prevent transcriptional memory from being inappropriately transmitted to the next generation. We asked if SPR-5, the C. elegans ortholog of the H3K4me2 demethylase LSD1/KDM1, plays a role in epigenetically reprogramming H3K4me2. We show that spr-5 mutants exhibit progressive sterility over many generations due to defects in oogenesis and spermatogenesis. These defects correlate with a progressive failure to erase H3K4me2 in the primordial germ cells, resulting in the misregulation of spermatogenesis-expressed genes due to the transgenerational accumulation of H3K4me2 at these loci. These results suggest that H3K4me2 can serve as an epigenetic memory and that LSD1/KDM1 demethylases play a critical role in the reprogramming of this memory in the germline, preventing inappropriate epigenetic information from being propagated from one generation to the next.

Chromatin computation: Epigenetic inheritance as a pattern reconstruction problem

“…Altering this steady-state balance pushes either towards the accumulation of the mark or its erasure ). This has been described most clearly in embryonic reprogramming (Katz et al, 2009;VerMilyea et al, 2009).…”

“…Furthermore, it has been reported repeatedly that particular epigenetic modifications can be gradually changed over generations through a number of different settings. In particular, these include the progressive reduction of higher histone methylation levels to lower methylation forms (Katan-Khaykovich and Struhl, 2005), epigenetic reprogramming (Jeong et al, 2007;Katz et al, 2009), epigenetic silencing / heterochromatin formation (Mutskov and Felsenfeld, 2003;Millar and Grunstein, 2006), and transcription-coupled histone modifications (Tippmann et al, 2012). Furthermore, histone modification gradients for a number of different modifications have been observed along a particular genomic region (for a review, see Henikoff and Shilatifard, 2011).…”

Genetics of germ cell development

“…[46][47][48] Likewise, loss of the LSD1 histone demethylase homolog spr-5 results in progressive failure to demethylate H3K4, impaired transcriptional repression, and cumulative sterility over multiple generations, while absence of the nanos homologs nos-1 and nos-2 causes premature reaccumulation of H3K4me2/3 in the embryonic germline and corresponding germline failure and sterility. 45,49 In D. melanogaster, germ cell precursors lacking nanos or the spr-5/LSD1…”

“…81,[131][132][133] Because of these features, and because they retain the potential to In worms, mutations in the histone demethylase gene, spr-5 (an LSD1/KDM1 homolog), cause a weak sterility phenotype that is passed on and becomes progressively more severe in subsequent generations, although the spr-5 coding and promoter DNA sequence does not change. 49 Meanwhile, mutations in three genes encoding a histone methylase complex, ash-2, wdr-5, and set-2, increase longevity through several generations of offspring, even when only the founding parental animal carries the mutant allele. 140 In D. melanogaster, an osmotic or heat stress stimulus can disrupt the activity of the transcription factor ATF-2 and deposition of the repressive histone modification H3K9me2, and this disruption can be transmitted to the next generation in a non-Mendelian manner.…”

A twist of fate: How a meiotic protein is providing new perspectives on germ cell development

“…spr-5 and met-2 mutants gradually accumulate H3K4me2 and lose H3K9me over many generations, leading to misexpression of spermatogenesis-enriched genes, reduced brood sizes, and sterility. 7,32,33 These studies highlight the importance of establishing an epigenetic "ground state" for germ cell development and illustrate the dramatic consequences of such an imbalance on fecundity.…”