MeCP2 regulates cell-type-specific functions of depressive-like symptoms in the nucleus accumbens.

Background: To identify new oncogenes that drive cancer development, we conducted an unbiased genome-scale screen for genes that can substitute for activated RAS in oncogenic transformation. We focused attention on one of the new potential oncogenes identified in this screen, Methyl CpG Binding Protein 2 (MECP2), which has no previously described role in malignancy and is amplified across ∼20% of all human cancers, and ∼30% of Triple-Negative Breast Cancer (TNBC). MECP2 is an X-linked gene known to bind methylated cytosines, and can act as a transcriptional repressor in this context. Recent studies show that it also acts as a transcriptional activator, likely through binding to another epigenetic modification of DNA, 5-hydroxymethylcytosine (5hmC). Results: MECP2 is as potent as activated RAS in conferring anchorage independent growth upon primary human mammary epithelial cells (hMECs) previously transduced with the SV40 early region and hTERT (N−RAS hMECs). MECP2 partially rescues the growth inhibition of RAS-addicted human cancer cell lines after the shRNA-mediated suppression of RAS. MECP2 expresses two spliced isoforms; experiments showed the short isoform activates the MAPK pathway, while the long isoform activates the PI3K pathway. Neither isoform alone can cause growth of N−RAS hMECs as a xenograft in nude mice; together, they can. The transformation and growth factor pathway induction activities of MECP2 absolutely require its DNA-binding activity. A number of TNBC cell lines have amplified, overexpressed MECP2, and of the first 13 TNBC patient-derived xenografts examined, 4 have MECP2 overexpression. Several TNBC cell lines that have amplified, overexpressed MECP2 show significant growth inhibition after shRNA-mediated downregulation of MECP2 (MECP2 addiction), while a breast cancer cell line without MECP2 overexpression showed no such inhibition. N−RAS hMECs transformed with MECP2 are an order of magnitude more sensitive to either of the DNA methylation inhibitors 5-azacytidine or decitabine than isogenic cells transformed by activated RAS, or isogenic cells without an additional transforming gene. Further, we find that combined treatment with the DNA methylation inhibitor 5-azacytidine and the HDAC inhibitor Trichostatin A is synergistic in our hMEC experimental system. Conclusion: MECP2 is a commonly amplified and overexpressed oncogene whose two splicing isoforms together recapitulate the major oncogenic functions of activated RAS. Because MECP2 requires DNA binding to methylated or hydroxymethylated cytosines for its tumor-promoting activities, DNA methylation inhibition with FDA-approved drugs may be therapeutic for tumors overexpressing MECP2. Citation Format: Daniel P Silver, Manish Neupane, Allison P Clark, Marc Vidal, David E Hill. MECP2 is a frequently amplified oncogene and potential therapeutic target in TNBC [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-05-04.

Methyl CpG binding protein-2 (MeCP2) is an essential epigenetic regulator in human brain development. Mutations in the MeCP2 gene have been linked to Rett syndrome, a severe X-linked progressive neurodevelopmental disorder, and one of the most common causes of mental retardation in females. MeCP2 duplication and triplication have also been found to affect brain development, indicating that both loss of function and gain in MeCP2 dosage lead to similar neurological phenotypes. Here, we used the Xenopus laevis visual system as an in vivo model to examine the consequence of increased MeCP2 expression during the morphological maturation of individual central neurons in an otherwise intact brain. Single-cell overexpression of wild-type human MeCP2 was combined with time-lapse confocal microscopy imaging to study dynamic mechanisms by which MeCP2 influences tectal neuron dendritic arborization. Analysis of neurons co-expressing DsRed2 demonstrates that MeCP2 overexpression specifically interfered with dendritic elaboration, decreasing the rates of branch addition and elimination over a 48 hour observation period. Moreover, dynamic analysis of neurons co-expressing wt-hMeCP2 and PSD95-GFP revealed that even though neurons expressing wt-hMeCP2 possessed significantly fewer dendrites and simpler morphologies than control neurons at the same developmental stage, postsynaptic site density in wt-hMeCP2-expressing neurons was similar to controls and increased at a rate higher than controls. Together, our in vivo studies support an early, cell-autonomous role for MeCP2 during the morphological differentiation of neurons and indicate that perturbations in MeCP2 gene dosage result in deficits in dendritic arborization that can be compensated, at least in part, by synaptic connectivity changes.

Precise levels of the transcriptional regulator Methyl CpG Binding Protein 2 (MeCP2) are known to be a key determinant for proper neurological function. Mutations in the MECP2 gene results in a disease known as Rett syndrome; in contrast, genetic duplication of MECP2 leads to a disorder known as MECP2 Duplication syndrome. The latter genetic neurodevelopmental disorder has a wide symptomology including stereotypy, seizures, cognitive deficits, and autism. In rodent models of MECP2 Duplication Syndrome in which MeCP2 is overexpressed, increases in glutamatergic synapse formation in hippocampal neurons occur, as well as impairments in hippocampal synaptic plasticity, a neurological phenomenon thought to be involved in memory and cognition. In accordance with this notion, MeCP2 overexpression causes memory and cognitive deficits in mice. Interestingly, the metabotropic glutamate receptor 3 (mGlu3) has been shown to be involved in regulating synaptic plasticity and cognitive behaviors in mice, and mGlu3 expression appears to correlate with MeCP2 expression levels in the brain. We hypothesized that that an upregulation of mGlu3 leads to an impairment in synaptic plasticity and cognitive deficits in MeCP2 overexpressing mice. To investigate the mechanisms by which MeCP2 overexpression induces neurophysiological impairments, a MeCP2‐Tg1 mouse model was used. Our results indicate that mGlu3 is upregulated the hippocampus of MeCP2‐Tg1 mice, correlating with an increase in MeCP2 protein expression. Electrophysiological experiments found that paired‐pulse facilitation was enhanced and input‐output intensity was reduced at the SC‐CA1 hippocampal synapse in the MeCP2‐Tg1 mice compared to wild‐type controls. Furthermore, (S)‐3,5‐Dihydroxyphenylglycine (DHPG) induced‐long term depression (LTD) was impaired in MeCP2‐Tg1 mice. Interestingly, an mGlu3 negative allosteric modulator, VU0650786, was capable of normalizing DHPG‐induced LTD to the level of that observed in wild‐type controls. These results suggest that overexpression of mGlu3 may contribute to synaptic plasticity impairments within the hippocampus of MeCP2‐Tg1 mice. Future experiments are aimed at elucidating behavioral correlates of these neurophysiological abnormalities and their underlying mechanisms.Support or Funding InformationT32NS007491 (BJS), rettsyndrome.org postdoctoral fellowship (RGG), Weatherstone predoctoral fellowship (BKS), T32 GM07628 (NF), R01 MH099269 (KAE), U54 MH084659 (CWL), R01 NS031373 (PJC), R21 MH102548 (CMN), Autism Speaks Treatment Award (CMN).

Epigenetic regulation has been implicated in the incubation of drug craving (the time-dependent increase in drug seeking after prolonged withdrawal from drug self-administration). There is little information available on the role of microRNAs in incubation of heroin craving. This study aimed to investigate the roles and mechanisms of miR-181a and methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) in incubation of heroin seeking. MiRNA sequencing was used to predict potential miRNAs, and miRNA profiles were performed in the NAc after 1day or 14days after withdrawal from heroin self-administration. Following 14days of heroin self-administration, rats were injected of lentiviral vectors into the NAc and evaluated for the effects of overexpression of miR-181a or knockdown of MeCP2 on non-reinforced heroin seeking after 14 withdrawal days. Lever presses during the heroin-seeking tests were higher after 14 withdrawal days than after 1day (incubation of heroin craving). miR-181a expression in NAc was lower after 14 withdrawal days than after 1day, and meCP2 expression in NAc was higher after 14days than after 1day. Luciferase activity assay showed that the 3'UTR of MeCP2 is directly regulated by miR-181a. Overexpression of miR-181a in NAc decreased heroin seeking after 14 withdrawal days and decreased MeCP2 mRNA and protein expression. Knockdown of MeCP2 expression in NAc by LV-siRNA-MeCP2 also decreased heroin seeking after 14 withdrawal days. Results indicate that incubation of heroin craving is mediated in part by time-dependent decreases in NAc miR181a expression that leads to time-dependent increases in MeCP2 expression. Our data suggest that NAc miR-181a and MeCP2 contribute to incubation of heroin craving.

Rett syndrome and MECP2 duplication syndrome are neurodevelopmental disorders that arise from loss of function and gain of function alterations in Methyl-CpG Binding Protein 2 (MeCP2) expression, respectively. Although there have been studies examining MeCP2 loss of function in animal models, there is limited information on MeCP2 overexpression in animal models. Here, we characterize a mouse line with MeCP2 overexpression restricted to neurons (Tau-Mecp2). This MeCP2 overexpression line shows motor coordination deficits, heightened anxiety, and impairments in learning and memory that are accompanied by deficits in long-term potentiation and short-term synaptic plasticity. Whole cell voltage clamp recordings of cultured hippocampal neurons from Tau-Mecp2 mice reveal augmented frequency of miniature excitatory postsynaptic currents with no change in miniature inhibitory postsynaptic currents indicating that overexpression of MeCP2 selectively impacts excitatory synapse function. Moreover, we show that alterations in transcriptional repression mechanisms underlie the synaptic phenotypes in hippocampal neurons from the Tau-Mecp2 mice. These results demonstrate the Tau-Mecp2 mouse line recapitulates many key phenotypes of MECP2 duplication syndrome and support the use of these mice to further study this devastating disorder.

(R,S)-ketamine is known to elicit persistent prophylactic effects in rodent models of depression. However, the precise molecular mechanisms underlying its action remain elusive. Using RNA-sequencing analysis, we searched for novel molecular target(s) that contribute to the prophylactic effects of (R)-ketamine, a more potent enantiomer of (R,S)-ketamine in chronic restraint stress (CRS) model. Pretreatment with (R)-ketamine (10 mg/kg, 1 day before CRS) significantly ameliorated body weight loss, increased immobility time of forced swimming test, and decreased sucrose preference of sucrose preference test in CRS-exposed mice. RNA-sequencing analysis of prefrontal cortex (PFC) revealed that several miRNAs such as miR-132-5p might contribute to sustained prophylactic effects of (R)-ketamine. Methyl CpG binding protein 2 (MeCP2) is known to regulate brain-derived neurotrophic factor (BDNF) expression. Quantitative RT-PCR confirmed that (R)-ketamine significantly attenuated altered expression of miR-132-5p and its regulated genes (Bdnf, Mecp2, Tgfb1, Tgfbr2) in the PFC of CRS-exposed mice. Furthermore, (R)-ketamine significantly attenuated altered expression of BDNF, MeCP2, TGF-β1 (transforming growth factor β1), and synaptic proteins (PSD-95, and GluA1) in the PFC of CRS-exposed mice. Administration of agomiR-132-5p decreased the expression of Bdnf and Tgfb1 in the PFC, resulting in depression-like behaviors. In contrast, administration of antagomiR-132-5p blocked the increased expression of miR-132-5p and decreased expression of Bdnf in the PFC of CRS-exposed mice, resulting in antidepressant-like effects. In conclusion, our data show a novel role of miR-132-5p in the PFC underlying depression-like phenotypes in CRS model and the sustained prophylactic effects of (R)-ketamine.

Normal levels of the methyl CpG-binding protein 2 (MeCP2) are critical to neurologic functioning, and slight alterations result in intellectual disability and autistic features. It was hypothesized that children with MECP2 duplication (overexpression of MeCP2) and Rett syndrome (underexpression of MeCP2) would exhibit distinct electroencephalographic (EEG) indices of auditory stimulus discrimination. In this study, gamma-band oscillatory responses to familiar and novel voices were examined and related to social functioning in 17 children (3-11 years old) with MECP2 duplication (n = 12) and Rett syndrome (n = 5). Relative to the stranger's voice, gamma activity in response to the mother's voice was increased in MECP2 duplication but decreased in Rett syndrome. In MECP2 duplication, greater mother versus stranger differences in gamma activity were associated with higher social functioning. For the first time, brain responses in a passive voice discrimination paradigm show that overexpression and underexpression of MeCP2 have differential effects on cortical information processing.

BackgroundIncreasing evidence suggests that aberrant methylation is involved in 5-fluorouracil (5-FU) resistance in gastric cancer (GC). Our previous work has identified that Methyl-CpG binding protein 2 (MeCP2) promotes GC progression by binding to the methylation sites of promoter regions of specific genes to affect the downstream signaling pathways. However, the function and molecular mechanisms of MeCP2 in GC 5-FU resistance remain unclear.MethodsWe detected the expression of MeCP2 in 5-FU-resistant GC cells and examined cell behaviors when MeCP2 was silenced. The molecular mechanisms were explored through chromatin immunoprecipitation (ChIP)-qRT-PCR, luciferase reporter assay, clinical tissue samples analysis, and in vivo tumorigenicity assay.ResultsMeCP2 was up-regulated in 5-FU-resistant GC cells. Knockdown of MeCP2 enhanced the sensitivity of the cells to 5-FU. Moreover, MeCP2 promoted NOX4 transcription in the cells by binding to the promoter of NOX4. Silencing NOX4 rescued the inductive effect of MeCP2 overexpression on 5-FU sensitivity of GC cells and reduced the expression of NOX4 and PKM2 in MeCP2 overexpressed 5-FU-resistant GC cells. In addition, our in vivo experiments demonstrated that MeCP2 knockdown enhanced 5-FU sensitivity in tumors.ConclusionMeCP2 confers 5-FU resistance in GC cells via upregulating the NOX4/PKM2 pathway, which may lead to a promising therapeutic strategy for GC.

Several X-linked neurodevelopmental disorders including Rett syndrome, induced by mutations in the MECP2 gene, and fragile X syndrome (FXS), caused by mutations in the FMR1 gene, share autism-related features. The mRNA coding for methyl CpG binding protein 2 (MeCP2) has previously been identified as a substrate for the mRNA-binding protein, fragile X mental retardation protein (FMRP), which is silenced in FXS. Here, we report a homeostatic relationship between these two key regulators of gene expression in mouse models of FXS (Fmr1 Knockout (KO)) and Rett syndrome (MeCP2 KO). We found that the level of MeCP2 protein in the cerebral cortex was elevated in Fmr1 KO mice, whereas MeCP2 KO mice displayed reduced levels of FMRP, implicating interplay between the activities of MeCP2 and FMRP. Indeed, knockdown of MeCP2 with short hairpin RNAs led to a reduction of FMRP in mouse Neuro2A and in human HEK-293 cells, suggesting a reciprocal coupling in the expression level of these two regulatory proteins. Intra-cerebroventricular injection of an adeno-associated viral vector coding for FMRP led to a concomitant reduction in MeCP2 expression in vivo and partially corrected locomotor hyperactivity. Additionally, the level of MeCP2 in the posterior cortex correlated with the severity of the hyperactive phenotype in Fmr1 KO mice. These results demonstrate that MeCP2 and FMRP operate within a previously undefined homeostatic relationship. Our findings also suggest that MeCP2 overexpression in Fmr1 KO mouse posterior cerebral cortex may contribute to the fragile X locomotor hyperactivity phenotype.

The MECP2 gene is located in the Xq28, which encodes for methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 gene is the primary cause of postnatal neurodevelopmental disorder, Rett syndrome (RTT) (loss-of-function). In contrast the over expression of MECP2 leads to duplication syndrome (gain-of-function). In both cases, gain and loss-of function of MECP2 leads to neurological disorders. In the first part of the thesis, we attempted to characterize the pathomechanism associated with human R270X mutation in MECP2, which is one of the most frequent mutation in RTT cohorts. The R270X mutation is located within the transcriptional repression domain- nuclear localization signals (TRD-NLS) of MeCP2 protein. This nonsense mutation exhibits severe phenotype with higher mortality rate as compared to the other mutations in RTT cohorts. To evaluate the molecular and functional role of R270X mutation, we generated a Mecp2R270_EGFP transgenic mouse by BAC recombineering technology, which is equivalent to human R270X mutation. The Mecp2R270_EGFP transgenic mouse showed similar pattern of expression as compared to the endogenous MeCP2. Further, we bred the Mecp2R270_EGFP transgenic male mouse with Mecp2 knockout female to obtain Mecp2R270 knockin (KI) mouse. Phenotypical evaluation revealed no neurological impairment in Mecp2R270_EGFP transgenic mice, but KI mice were positive for hindlimb clasping. In addition, we observed no difference in neurite length, area of soma and spine density between wildtype and Mecp2R270_EGFP neurons, but detected reduced neurite length, soma size and spine number in KI neurons. From our experimental data, we conclude that MeCP2R270_EGFP protein has a deleterious effect on neuronal morphology and alters the spine density. In the second part of the thesis, we generated a Mecp2 transgenic mouse model to determine the MECP2 dosage effect on duplication syndrome. The generated Mecp2WT_EGFP transgenic mice mildly overexpressed MeCP2 (~1.5X) (MeCP2 transgenic with endogenous) From our extensive behavioral analyzes, we observed increased aggressiveness and higher seizures in Mecp2WT_EGFP transgenic mice propensity after treatment with epileptogenic compound pentylenetetrazole (PTZ). Furthermore, induction of Mecp2WT_EGFP transgenic cultured neurons with PTZ caused increase calcium amplitude with a higher frequency. Additionally, the ex vivo and in vivo evaluation of neuronal parameters of hippocampal neurons revealed an increased area of soma, reduced tertiary branching sites and increased spine density in Mecp2WT_EGFP transgenic mouse. Collectively, our results suggest that mild MeCP2 overexpression in mice leads to epileptic seizures as a first symptom. Furthermore, precise MeCP2 dosage is necessary for proper neurodevelopment in mice. In the third part of the thesis, we reported that the MeCP2 expression is not restricted only in the neurons but also expressed in astrocytes. Recent studies highlighted the role of MeCP2 in astrocytes. The co-cultured assay system with Mecp2 null astrocytes together with wild type neurons displayed shorter and small number of dendrites. These findings suggested the unknown secreted factor(s) from Mecp2 deficient astrocytes cause toxic effect to the neighboring neurons in non-cell-autonomous manner. In order to determine and characterize the MeCP2 targets in astrocytes, we performed proteomic analysis and characterized ~5000 different proteins in astrocytes with three independent technical repeats. Our proteomic analysis revealed 69 up-regulated and 29 down-regulated proteins in knockin (KI) and 50 up-regulated and 32 down-regulated proteins in knockout (KO), when compared to wildtype astocytes. The identified Mecp2 target proteins from proteomic analysis revealed that MeCP2 is involved in cell adhesions through desmosomal proteins (Dsp and Pkp1), regulation of reactive oxygen species (ROS) (Txn2) and glutamate homeostasis via Slc25a18 in astrocytes. We could validate the differential expression of Mecp2 target proteins such as Dsp and Pkp1 in Mecp2 knockout astrocytes compared to wild type astrocytes through Western blot analysis. After validating the proteomic data, in future an ex vivo assay can be established to test the effect of non-cell autonomous astrocytes factors identified through proteomics approach. Establishing the role of glial dysfunction in RTT pathogenesis could provide a new avenue for understanding RTT and will assist us in developing novel therapy for this disease.

Increasing evidence indicates that an imbalance in oncogenes is implicated in cancer chemotherapy resistance. Methyl-CpG binding protein 2 (MeCP2), which acts as a major epigenetic regulator of the expression of various genes, is involved in the carcinogenesis and progression of gastric cancer. However, is it not known whether the role of MeCP2 is vital in acquired cisplatin resistance in gastric cancer. This study aimed to determine whether inhibition of MeCP2 expression could sensitize DDP-resistant GC cells to DDP and elucidate the underlying molecular mechanism. qRT-PCR and western blotting were used to evaluate MeCP2 expression in DDP-resistant GC cells. Subsequently, cell viability, colony formation, cell cycle, apoptosis, and tumorigenicity assays were performed to explore the in vitro and in vivo roles of MeCP2. Chromatin immunoprecipitation- qPCR and luciferase reporter assays were used to identify whether 3-phosphoinositide-dependent protein kinase 1 (PDK-1) was a direct target gene of MeCP2. MeCP2 was upregulated in malignant DDP-resistant cells compared to non-DDP-resistant GC cells or normal gastric epithelial cells. MeCP2 knockdown increased the sensitivity of DDP-resistant GC cells to DDP, resulting in reduced cell growth, G0/G1 phase arrest, and increased apoptosis, whereas MeCP2 overexpression attenuated DDP sensitivity of DDP-resistant GC cells. In addition, MeCP2 knockdown enhanced DDP sensitivity in vivo. MeCP2 elevated PDK-1 expression by binding to CpG sites in promoter regions, and inhibition of PDK-1 reversed the inductive effect of MeCP2 overexpression on DDP resistance in GC cells. These findings indicate that silencing of MeCP2 may potentiate DDP-induced cell death, thereby providing a promising therapeutic strategy for GC.

The methyl CpG-binding protein 2 (MECP2) gene has copy-number gain in a number of human cancers and functions as an oncogene through an unusual epigenetic mechanism. We explored the possibility that MECP2 might be a therapeutic target and whether its epigenetic mode of action is amenable to specific therapy. Constitutively expressed or inducible lentiviral short hairpin RNA directed at MECP2 in human triple-negative breast cancer (TNBC) cell lines with high or low level of MECP2 protein were grown as xenografts to assess oncogene addiction. We next evaluated the effect of DNA methylation inhibitors or histone deacetylase inhibitors on monolayer or soft agar growth of isogenic human mammary epithelial cells with or without MECP2 overexpression and xenograft growth of MECP2-dependent or MECP2-independent human TNBC or lung cancer cell lines. We then investigated the mechanism of MECP2-induced activation of the MAPK pathway and assessed the effect of drug treatment. Human cancer cell lines with MECP2 overexpression show MECP2 dependence, and epigenetic drugs are effective in these models. Activated RAS and other activators of the MAPK pathway caused resistance to these therapies, giving insight into their novel mode of action and demonstrating specificity. The kinase PAK3 is important for MECP2-mediated induction of the MAPK pathway, is modulated by epigenetic drugs affecting MECP2 action as expected, and may itself be a therapeutic target for MECP2-driven cancers. These preclinical studies show that tumors overexpressing MECP2 might benefit from epigenetic therapy targeting MECP2 function and demonstrate a novel mechanism of action for these drugs.

Epigenetic mechanisms are fundamental for shaping the activity of the central nervous system (CNS). Methyl-CpG binding protein 2 (MECP2) acts as a bridge between methylated DNA and transcriptional effectors responsible for differentiation programs in neurons. The importance of MECP2 dosage in CNS is evident in Rett Syndrome and MECP2 duplication syndrome, which are neurodevelopmental diseases caused by loss-of-function mutations or duplication of the MECP2 gene, respectively. Although many studies have been performed on Rett syndrome models, little is known about the effects of an increase in MECP2 dosage. Herein, we demonstrate that MECP2 overexpression affects neural tube formation, leading to a decrease in neuroblast proliferation in the neural tube ventricular zone. Furthermore, an increase in MECP2 dose provokes premature differentiation of neural precursors accompanied by greater cell death, resulting in a loss of neuronal populations. Overall, our data indicate that correct MECP2 expression levels are required for proper nervous system development.

Sympathetic activation in heart failure (HF) is typically considered cardiotoxic. Indeed, class I recommended drugs in HF with reduced ejection fraction all inhibit direct or indirect effects of sympathetic activation. Contrary to this paradigm, Mayer et al1 in this issue of Circulation Research provide evidence for a cardioprotective pathway mediated by activation of cardiac myocyte adrenergic receptors (ARs). This novel pathway involves β1- and α1-ARs, miR-212/132, and the epigenetic regulator, methyl CpG-binding protein 2 (MeCP2), the X-linked gene mutated in Rett Syndrome, a neurological disorder. The Figure outlines the model and the data from the article that support it. Figure. Left , The model suggested in the study by Mayer et al.1 Right , The supporting data. Note that the beneficial effects of methyl CpG-binding protein 2 (MeCP2) repression are mostly deduced from the adverse effects seen with MeCP2 overexpression. AR indicates adrenergic receptor; cKO, cardiac knockout; HF, heart failure; iTG, inducible transgenic; KO, knockout; miR, microRNA; NE, norepinephrine; PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; and TAC, transverse aortic constriction. Article, see p 622 The initial focus of the study was mechanisms that facilitate reverse remodeling or cardiac recovery with unloading. Accordingly, the group used a clever approach of screening mRNAs that were differentially expressed between mouse transverse aortic constriction (TAC) and unloading by TAC reversal, ie, removing the constriction at a second surgery (rTAC). They identified MeCP2 as a gene that was repressed by TAC and normalized after TAC reversal. The same MeCP2 pattern was seen in humans with HF with reduced ejection fraction, where MeCP2 was repressed in failing hearts and normalized after unloading by left ventricular assist device. Among 30 genes with similar regulation in the human heart, MeCP2 was predominant in mouse myocytes versus nonmyocytes and was studied further. MeCP2 was also repressed in …

Effects of MeCP2 on chronic seizures and cognitive function in mice with temporal lobe epilepsy.