Histone Demethylase AMX-1 Regulates Fertility in a p53/CEP-1 Dependent Manner

Abstract

Histone methylation shapes the epigenetic configuration and adjusts multiple fundamental nuclear processes, including transcription, cell cycle control and DNA repair. The absence of histone demethylase LSD1/SPR-5 leads to progressive fertility defects as well as a reduction in brood size. Similarly, C. elegans LSD2 homolog AMX-1 has been implicated in regulating H3K4me2 and maintaining interstrand crosslinks (ICL) susceptibility. However, the mechanisms of how lack of AMX-1 induces sterility have not been addressed so far. This study investigated the histone demethylase AMX-1 in C. elegans and uncovered how amx-1 contributes to sterility in a p53/CEP-1 dependent manner. We show that while sterility in spr-5 mutants exhibited progressive over generations, amx-1 mutants displayed non-transgenerational fertility defects. Also, amx-1 mutants exhibited a reduced number of sperms and produced low brood size (LBS) or sterile worms that retain neither sperms nor germline nuclei, suggesting that fertility defects originated from germline development failure. Surprisingly, sterility exhibited in amx-1 was mediated by p53/CEP-1 function. Consistent with this result, upregulation of Piwi expression in amx-1 mutants suggested that AMX-1 is essential for germline development by regulating Piwi gene expressions. We propose that AMX-1 is required for proper Piwi expression and transposon silencing in a p53/CEP-1 dependent manner; thus, the absence of AMX-1 expression leads to defective meiotic development and sterility. This study elucidates how LSD2/AMX-1 contributes to sterility, therefore, expanding the boundaries of histone demethylase function.

LSD2 Is an Epigenetic Player in Multiple Types of Cancer and Beyond

“…Recent studies in C. elegans have elucidated the roles of LSD2 homolog AMX-1 and its potential implications in DNA repair mechanisms [4,15]. Lack of AMX-1 expression results in embryonic lethality, decreased brood size, and disrupted organization of premeiotic tip germline nuclei.…”

“…Implicated in various cancers, with roles in promotion or suppression Human cancer involvement: lung, breast, pancreatic, liver and colorectal cancer tissues or cell lines [23][24][25][28][29][30] Involved in establishing DNA methylation imprints during oogenesis Epigenetic regulation during oogenesis [19] Implicated in non-transgenerational fertility defects in C. elegans Role in fertility defects in model system [4] Involved in ICL DNA damage repair in C. elegans…”

“…Histone demethylases can be classified into two families based on their enzymatic action: amine oxidase demethylases (LSD1/KDM1A and LSD2/KDM1B) and Jumonji C (JmjC) family [1][2][3][4][5]. The first histone demethylase to be discovered was lysine-specific demethylase 1 (LSD1), which is a homologue of flavin-containing amine oxidases [6,7].…”

LSD2 is an Epigenetic Player in Multiple Types of Cancer and Beyond

“…Histone demethylases can be classified into two families based on their enzymatic action: amine oxidase demethylases (LSD1/KDM1A and LSD2/ KDM1B) and Jumonji C (JmjC) family [1][2][3][4][5].…”

Experimental Insights into the Interplay between Histone Modifiers and p53 in Regulating Gene Expression

“…The interplay between histone modifiers, such as histone acetyltransferases/deacetylase and histone methyltransferases/demethylase, and p53 is crucial for regulating gene expression, maintaining genomic stability, facilitating chromatin remodeling, and promoting DNA repair. The synergy between the two ensures proper cellular responses to DNA damage, stress signals, and other regulatory cues [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. p53 is the guardian of the genome, whose activity is implicated in most types of cancers, so its post-transcriptional modifications have been extensively studied [ 16 , 17 , 18 ].…”