The Catalytic-Dependent and -Independent Roles of Lsd1 and Lsd2 Lysine Demethylases in Heterochromatin Formation in Schizosaccharomyces pombe

Abstract

In eukaryotes, heterochromatin plays a critical role in organismal development and cell fate acquisition, through regulating gene expression. The evolutionarily conserved lysine-specific demethylases, Lsd1 and Lsd2, remove mono- and dimethylation on histone H3, serving complex roles in gene expression. In the fission yeast Schizosaccharomyces pombe, null mutations of Lsd1 and Lsd2 result in either severe growth defects or inviability, while catalytic inactivation causes minimal defects, indicating that Lsd1 and Lsd2 have essential functions beyond their known demethylase activity. Here, we show that catalytic mutants of Lsd1 or Lsd2 partially assemble functional heterochromatin at centromeres in RNAi-deficient cells, while the C-terminal truncated alleles of Lsd1 or Lsd2 exacerbate heterochromatin formation at all major heterochromatic regions, suggesting that Lsd1 and Lsd2 repress heterochromatic transcripts through mechanisms both dependent on and independent of their catalytic activities. Lsd1 and Lsd2 are also involved in the establishment and maintenance of heterochromatin. At constitutive heterochromatic regions, Lsd1 and Lsd2 regulate one another and cooperate with other histone modifiers, including the class II HDAC Clr3 and the Sirtuin family protein Sir2 for gene silencing, but not with the class I HDAC Clr6. Our findings explore the roles of lysine-specific demethylases in epigenetic gene silencing at heterochromatic regions.

Proteomic analysis of differentially expressed whey proteins in Saanen goat milk from different provinces in China using a data-independent acquisition technique

“…The 3 compared pairs had 1 common DEP, histone H4, which had the highest abundance in samples collected from GD. Histones are involved in several cellular processes such as transcription, repair, and recombination (Marayati et al, 2020). A high level of histone H4 is one of the important risk factors leading to an increased probability of death in patients with Zhao et al: PROTEOMICS ANALYSIS OF DIFFERENTIALLY EXPRESSED PROTEINS IN GOAT MILK sepsis, and it is also considered an effective biomarker for evaluating sepsis (Lu et al, 2020).…”

The Fission Yeast Mating-Type Switching Motto: “One-for-Two” and “Two-for-One”

“…In fission yeast, the Lsd1/2 activities prevent H3K9 methylation at heterochromatin boundaries and telomeric regions and were also found enriched on highly expressed genes (88,113,114,119). Lsd2, Phf1, and Phf2 are essential, but the lsd1D strain is viable and exhibits strongly reduced proliferation (120). However, the demethylase dead alleles of Lsd1/2 (single or combined) remain viable, and the double mutant strain exhibits a reduced pausing activity at MPS1 independently of Clr4, the sole H3K9 methyltransferase in fission yeast, indicating that the methylation of H3K9 is required neither for viability nor for pausing at MPS1 (88,111).…”

Histone Demethylase Modulation: Epigenetic Strategy to Combat Cancer Progression

“…LSD2/AOF1/KDM1B is a different member of this amine oxidase protein family, and although structurally comparable to LSD1, LSD2 does not participate in the complexes that represent chromatin [ 45 ]. LSD2’s linkage to the control of the inflammatory process through NF-kB and its dependence on the mono- and di-methylation of histone H3K4 are crucial for the production of induced pluripotent stem cells, and are also connected to genomic imprints [ 109 , 110 ].…”