Table 1.
Summary showing studies of RELN methylation relevant to neurobiologya.
| Reference | Locationb | Species | Tissue | Design | Method | Result |
|---|---|---|---|---|---|---|
| Abdolmaleky et al. (2005) | Promoter: below −700 bp | Human | Frontal Lobe | RELN methylation in SZ vs. Con were compared | Bisulfite seq, Methylation specific PCR | RELN promoter is hypermethylated in SZ |
| Aberg et al. (2014) | First Intron | Human | Whole Blood | RELN methylation in SZ vs. Con were compared | Methyl Binding Domain- profiling | RELN is hypermethylated in SZ |
| Blaze et al. (2013) | Promoter | Rats | Medial Prefrontal Cortex | Comparison of methylation status at the Reln promoter as a function of post-natal maltreatment or nurturing care | Methylation specific PCR | Reln methylation varies by condition, age and sex |
| Chen et al. (2002) | Promoter: below −527 bp | Human | NT2 Cells | RELN methylation in differentiated vs. control neuroprogenitor cells in vitro were examined | Bisulfite seq | RELN hypermethylation in NT2 cells that is demethylated on differentiation |
| Dong et al. (2007) | Promoter: −520 to −198 bp | Mouse | Frontal Cortex | Methionine (MET) induced hypermethylation of the RELN promoter was examined and the effects of VPA and MS-275 on this methylation in vivo were evaluated | Methylation specific PCR | MET induces RELN methylation, while VPA and MS-275 reverse this methylation |
| Dong et al. (2016) | Promoter: −220 to +70 bp | Mouse | Frontal Cortex | PRS mice were examined for changes in Reln promoter methylation or hydroymethylation at PND 75 following either vehicle (VEH), clozapine (CLZ) or haloperidol (HAL) | MeDIP, hMeDIP | At PND 75, PRS strongly induces RELN promoter hypermethylation and, to a lesser extent hydroxyl methylation, of the Reln promoter. CLZ, but not HAL, attenuates the PRS-induced hypermethylation |
| Grayson et al. (2005) | Promoter: below −527 bp | Human | BA 9 and 10 | RELN methylation in SZ vs. Con were compared | Bisulfite seq | RELN is hypermethylated in SZ |
| Kobow et al. (2009) | Promoter: below −500 to +100 bp | Human | Hippocampus | Human temporal lobe epilepsy (TLE) biopsy specimens vs. autopsied control tissue were compared | Bisulfite seq | RELN promoter hypermethylation was observed in TLE biopsies |
| Kundakovic et al. (2009) | Promoter: below −250 bp | Human | NT2 Cells | The effect of the HDAC inhibitor, MS-275, on RELN promoter methylation was determined | MeDIP followed by qPCR | MS-275 induces RELN promoter demethylation |
| Levenson et al. (2006) | Promoter: between −1000 and −500 bp | Mouse | Hippocampal Slice Preparation | The response of neurons in slices to the effects of Protein Kinase C (PKC) activation by phorbol esters and or by inhibitors of DNA methylation | Methylation specific PCR | Reln promoter methylation is decreased by inhibitors of DNA methylation and activators of PKC |
| Lintas and Persico (2010) | Promoter: below −413 bp | Human | BA 41 and 42 | RELN promoter methylation was examined in pre- and post-pubertal post-mortem brain from non-psychiatric subjects | Bisulfite seq | Post-pubertal RELN promoter is hypermethylated compared with pre-pubertal RELN |
| Matrisciano et al. (2011) | Promoter: −423 to −252 bp | Mouse | Frontal Cortex | PRS mice were examined for methylation vs. non-stressed mice and the effect of LY379268 on this methylation | MeDIP | PRS mice showed Reln promoter methylation which was reduced by LY379268 |
| Matrisciano et al. (2013) | Promoter: −432 to −252 bp | Mouse | Frontal Cortex | PRS mice were analyzed for changes in Reln promoter methylation and hydroxymethylation vs. Con | MeDIP and hMeDIP | PRS mice showed elevated Reln promoter methylation and hydroxymethylation at PND 60 |
| Mill et al. (2008) | Promoter | Human | Frontal Cortex | RELN methylation in SZ vs. BD vs. Con were compared | Pyrosequencing | No change between groups |
| Mitchell et al. (2005) | Promoter: below −500 bp | Human | NT2 Cells | Determined the effects of HDAC and DNMT inhibitors on RELN promoter methylation | Bisulfite seq | TSA, VPA and AZA induces RELN hypomethylation |
| Noh et al. (2005) | Promoter: −340 to +140 bp | Mouse | Cortical Neurons | MET was used to manipulate RELN promoter methylation in vitro | Bisulfite seq | MET induced RELN promoter hypermethylation |
| Palacios-Garcia et al. (2015) | Promoter: −786 to −625 bp | Rats | Whole Cortex Cultured Neurons | PRS rats were analyzed for changes in Reln promoter methylation in vivo and in vitro | Methylation sensitive restriction enzyme PCR | Reln promoter methylation is increased in newborn PRS rats and in cultured neurons in vitro |
| Qin et al. (2011) | Promoter | Rat | Hippocampus | The effects of maternal deprivation on Reln promoter methylation were examined | Methylation specific PCR | Maternal deprivation facilitated increased Reln promoter methylation |
| Sui and Li (2010) | Promoter: −700 to −400 bp | Rat | Hippocampus | Promoter methylation was analyzed in rats with perinatal hypothyroidism at PND 1 through 60 | Methylation specific PCR | Hypothyroid rats show elevated Reln promoter methylation at PND 1, 5 and 15 relative to Con |
| Sui et al. (2012) | Promoter | Rat | Medial Prefrontal Cortex | Promoter methylation was analyzed following the induction of LTP as compared with Con | Methylation specific PCR | High frequency stimulations induce DNA demethylation at the Reln promoter vs. Con |
| Tremolizzo et al. (2002) | Promoter: −340 to +160 bp | Mouse | Frontal Cortex | The effects of VPA treatment on the MET-induced hypermethylation of the RELN promoter were evaluated | Bisulfite seq | Methionine induces RELN methylation, while VPA reverses this effect |
| Zhubi et al. (2014) | Promoter: −220 to +70 bp | Human | Cerebellum | Reln promoter methylation and hydroxymethylation were analyzed in autism spectrum disorder (ASD) vs. typically developed subjects (Con) | MeDIP and hMeDIP | While RELN promoter methylation levels are unchanged between ASD and Con, 5hmC content at the promoter is increased |
aThe above studies do not include at least one report (Tochigi et al., 2008) that showed no detectable RELN promoter methylation in either SZ or control subjects by pyrosequencing. In addition, there are numerous studies showing that elevated RELN promoter methylation is associated with poor prognosis in various types of cancers. We apologize for any relevant studies that were inadvertently omitted from this list. bFor precise locations of the RELN methylation see the associated reference. The locations provided are approximate and if no coordinates are indicated, then the information was not in the original report. For example, Promoter (without additional information) indicates that the authors specified the RELN promoter without giving additional coordinates. ASD, Autism spectrum disorder; Bisulfite seq, Bisulfite sequencing; CLZ, Clozapine; Con, Control; HAL, Haloperidol; hMeDIP, Hydroxymethyl DNA immunoprecipitation; LTP, Long-term potentiation; MeDIP, Methyl DNA immunoprecipitation; NT2 cells, Ntera2 cells; PCR, Polymerase chain reaction; PKC, Protein kinase C; PND, Post-natal day; PRS, Pre-natal restraint stress; TLE, Temporal lobe epilepsy; VEH, Vehicle; VPA, Valproic acid.