Epigenetic control of embryonic renal cell differentiation by L1 retrotransposon

Abstract

Background L1 retroelements may play a central role in morphogenesis through epigenetic mechanisms involving recruitment of chromatin modifying protein complexes. Retroelements are repressed in terminally differentiated cells, and highly active in embryonic, undifferentiated, and transformed cells. It is not clear if the modulation of differentiation by L1 is a “cause” or “effect”. The aim of this study was to determine if murine embryonic kidney cells of clonal origin (mK4 cells) harbor retrotransposition events upon ectopic expression of L1, and the impact of L1 on embryonic kidney cell differentiation. Given that L1 is reactivated by AHR ligands, we also sought to investigate the effects of benzo(a)pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the genetic network of mK4 cells. Methods mK4 cells overexpressing human LIRP were assessed for changes in proliferation and expression of molecular markers of cellular differentiation. Results L1RP increased proliferation rates and markedly downregulated differentiation programming in mK4 cells. These genetic alterations were recapitulated by exogenous activation of L1 by AHR ligands. Conclusion L1 regulates nephrogenesis in vitro via both insertional and non-insertional mechanisms that disrupt mesenchymal to epithelial transition. Thus, a feedback loop involving L1, WT1 and AHR may play a role in regulation of kidney morphogenesis.

Reprogramming of the HepG2 genome by long interspersed nuclear element‐1

“…These pathways are closely linked to malignant transformation and tumorigenesis. These findings are in keeping with previous reports showing that siRNA knockdown of ORF2 reduces the proliferation of human hepatoma cell lines in a dose dependent manner (Yang et al., 2003), while ORF1p is abundantly expressed in invasive malignant breast carcinoma compared with nonmalignant carcinoma, or normal tissues (Kuo et al., 1998), and ectopic expression of L1 modulates differentiation programs of embryonic kidney cells (Ramos et al., 2011). An emerging theme is the use of RT inhibitors for inhibition of tumor growth in vivo (Sciamanna et al., 2005), with tumors totally arrested or considerably reduced when tumorigenic cell lines (A‐375 melanoma, PC3 prostate carcinoma, H69 small lung carcinoma, and HT29 colon carcinoma) treated with efavirenz, an RT inhibitor (Sciamanna et al., 2005).…”

“…L1 s are highly active during genetic sorting in early embryogenesis, but undergo epigenetic silencing via DNA methylation and heterochromatin formation of pericentromeric and telomeric regions within the genome. With the exception of mutational inactivation of selected loci (Goodier and Kazazian, 2008; Montoya‐Durango et al., 2009), or the silencing of neighboring regions via chromatin remodeling (Ramos et al., 2011), little is understood about the complexity of biological control exerted by L1s . In the present study, we establish for the first time key elements of the functionality of L1 within the mammalian genome, and elucidate the biological connectivity of genetic elements within a regulatory network that reprograms the HepG2 genome.…”

Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

“…Methylation/demethylation of genes is one of the powerful epigenetic modifications that regulates gene transcription (2,3). Methylation/demethylation profiles of many genes have been linked with normal development and differentiation (4 -6) as well as with cancer initiation and progression.…”

AHR Regulates WT1 Genetic Programming during Murine Nephrogenesis

“…It is interesting to note that although the molecular and cellular phenotypes elicited by BaP in the developing kidney are largely mediated by proteasome-mediated downregulation of AHR (25), BaP arrested metanephric differentiation at an earlier point than AHR null mice. These settled differences likely reflect the complexity of the biological response since disruption of metanephric differentiation by the carcinogen is known to involve AHR-dependent reactivation of repetitive sequences within the embryonic kidney genome (26,27).…”