Regulation of Heterochromatin Transcription by Snail1/LOXL2 during Epithelial-to-Mesenchymal Transition

Abstract

Although heterochromatin is enriched with repressive traits, it is also actively transcribed, giving rise to large amounts of noncoding RNAs. Although these RNAs are responsible for the formation and maintenance of heterochromatin, little is known about how their transcription is regulated. Here, we show that the Snail1 transcription factor represses mouse pericentromeric transcription, acting through the H3K4 deaminase LOXL2. Since Snail1 plays a key role in the epithelial-to-mesenchymal transition (EMT), we analyzed the regulation of heterochromatin transcription in this process. At the onset of EMT, one of the major structural heterochromatin proteins, HP1α, is transiently released from heterochromatin foci in a Snail1/LOXL2-dependent manner, concomitantly with a downregulation of major satellite transcription. Moreover, preventing the downregulation of major satellite transcripts compromised the migratory and invasive behavior of mesenchymal cells. We propose that Snail1 regulates heterochromatin transcription through LOXL2, thus creating the favorable transcriptional state necessary for completing EMT.

Beyond the histone tale: HP1α deregulation in breast cancer epigenetics

“…Thus, a HP1a release from chromatin is probably necessary to permit the heterochromatin reorganization occurring during EMT. 111 Since HP1a association to pericentric heterochromatin requires RNA components derived from these sites the results are consistent with an underlying Snail1 mediated down-regulation of such heterochromatic derived transcripts (Fig. 2, panel 1).…”

“…111 Millanes-Romero, et al demonstrated that HP1a association to major satellite repeat sequences located in pericentric heterochromatin decreased during the initial steps of TGFb-induced EMT. 111 This effect was shown to be because of a Snail1-dependent transient release of HP1a proteins from pericentric heterochromatin, rather than an effect due to transcriptional downregulation of HP1a encoding mRNA from the CBX5-gene. Thus, a HP1a release from chromatin is probably necessary to permit the heterochromatin reorganization occurring during EMT.…”

“…2, panel 1). 111 Other means such as histone modifications and HP1a posttranslational modifications could participate in HP1a dynamics in heterochromatin association in EMT (Fig. 2).…”

Constitutive heterochromatin formation and transcription in mammals

“…At the onset of epithelial mesenchymal transition, SNAIL1 is rapidly upregulated and recruits LOXL2 to oxidize H3 at pericentromeres, leading to a transient downregulation of major satellite transcription. Interestingly, this coincides with a transient release of HP1α [109]. Once epithelial mesenchymal transition has completed, HP1α binding and major satellite transcription are re-established in mesenchymal cells.…”

RNAs — Physical and functional modulators of chromatin reader proteins

“…Several transcription factors such as Snail1, Pax3 or Pax9 and an amino oxidase, LOXL2 regulate transcription from these loci [35,36]. Suppression of expression by cooperative action of Snail1 and LOXL2 causes transient release of HP1α from heterochromatic foci, a process which is presumably necessary for heterochromatin reorganization to complete the EMT [36].…”