Protein degradation of Lsd1 is mediated by Bre1 yet opposed by Lsd1-interacting lncRNAs during fly follicle development.

Tissue development, homeostasis, and repair all require efficient progenitor expansion. Lysine-specific demethylase 1 (Lsd1) maintains plastic epigenetic states to promote progenitor proliferation while overexpressed Lsd1 protein causes oncogenic gene expression in cancer cells. However, the precise regulation of Lsd1 protein expression at the molecular level to drive progenitor differentiation remains unclear. Here, using Drosophila melanogaster oogenesis as our experimental system, we discovered molecular machineries that modify Lsd1 protein stability in vivo. Through genetic and biochemical analyses, an E3 ubiquitin ligase, Bre1, was identified as required for follicle progenitor differentiation, likely by mediating Lsd1 protein degradation. Interestingly, specific Lsd1-interacting long non-coding RNAs (LINRs) were found to antagonize Bre1-mediated Lsd1 protein degradation. The intricate interplay discovered among the Lsd1 complex, LINRs and Bre1 provides insight into how Lsd1 protein stability is fine-tuned to underlie progenitor differentiation in vivo.

Identification of Lsd1-interacting non-coding RNAs as regulators of fly oogenesis.

Lysine-specific demethylase 1 (Lsd1) plays a key role in balancing cell proliferation and differentiation. Lsd1 has been recently reported to associate with specific long noncoding RNAs (lncRNAs) to account for oncogenic gene expression in cancer cells. However, how lncRNA-Lsd1 interplay affects cell-specific differentiation remains elusive in vivo. Here, through Lsd1 specific RNA immunopecipitation sequencing (RIP-seq) experiments, we identify three long hairpin RNAs as Lsd1-interacting non-coding RNAs (LINRs) from fly ovaries. Knocking out LINR-1 and LINR-2 affects fly egg production, while each of the LINR deletion mutant females produce eggs with reduced hatch rate, indicating important functions of LINRs in supporting oogenesis. At the cellular level, LINR-2 regulates the differentiation of germline stem cells and follicle progenitors likely though modulating the expression and function of Lsd1 in vivo. Our identification of ovarian LINRs presents a physiological example of dynamic lncRNA-Lsd1 interplay that regulates stem cell/progenitor differentiation.