TET2 promotes anti-tumor immunity by governing G-MDSCs and CD8+ T-cell numbers.

The host immune response is a fundamental mechanism for attenuating cancer progression. Here we report a role for the DNA demethylase and tumor suppressor TET2 in host anti-tumor immunity. Deletion of Tet2 in mice elevates IL-6 levels upon tumor challenge. Elevated IL-6 stimulates immunosuppressive granulocytic myeloid-derived suppressor cells (G-MDSCs), which in turn reduce CD8+ T cells upon tumor challenge. Consequently, systematic knockout of Tet2 in mice leads to accelerated syngeneic tumor growth, which is constrained by anti-PD-1 blockade. Removal of G-MDSCs by the anti-mouse Ly6g antibodies restores CD8+ T-cell numbers in Tet2-/- mice and reboots their anti-tumor activity. Importantly, anti-IL-6 antibody treatment blocks the expansion of G-MDSCs and inhibits syngeneic tumor growth. Collectively, these findings reveal a TET2-mediated IL-6/G-MDSCs/CD8+ T-cell immune response cascade that safeguards host adaptive anti-tumor immunity, offering a cell non-autonomous mechanism of TET2 for tumor suppression.

Kdm1a promotes SCLC progression by transcriptionally silencing the tumor suppressor Rest.

Small cell lung carcinoma (SCLC) is one of the deadliest cancer types, with a 5-year survival rate less than 10%. Kdm1a/Lsd1 has recently been implicated as a potential therapeutic target for SCLC. However, the underlying molecular mechanism by which Kdm1a promotes the oncogenesis of SCLC has not been fully understood. Kdm1a is significantly elevated in most human SCLC specimens, whereas Rest, a tumor suppressor and neuronal repressive transcriptional factor, is typically inactivated. Knock-out of Kdm1a (Kdm1a-KO) in mouse SCLC cell lines resulted in the suppression of cell growth and soft agar colony formation. RNA-Seq analysis of the Kdm1a-KO cells revealed significant repression of a program of neuroendocrine signature genes, and conversely, a significant upregulation of a network of genes capable of inhibiting tumor cell growth. Rest was identified among the top 10 upregulated genes in Kdm1a-KO cells. The treatment of the SCLC cells with Kdm1a demethylase inhibitors resulted in a dramatic up-regulation of Rest similar to the extent of that in Kdm1a-KO cells. Importantly, accompanying the restored expression of the SCLC signature genes, knock-out of Rest in Kdm1a-KO cells rescued the restricted cell growth and soft agar colony formation. Taken together, these novel findings show that Kdm1a is a key transcriptional repressor of Rest, and that suppression of SCLC progression by the targeted inhibition of Kdm1a depends on the reactivation of Rest, suggesting a new strategy for effective SCLC treatment by targeting the Kdm1a/Rest molecular pathway.

The fusiform gyrus exhibits an epigenetic signature for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, and patients with advanced AD frequently lose the ability to identify family members. The fusiform gyrus (FUS) of the brain is critical in facial recognition. However, AD etiology in the FUS of AD patients is poorly understood. New analytical strategies are needed to reveal the genetic and epigenetic basis of AD in FUS. RESULTS: A complex of new analytical paradigms that integrates an array of transcriptomes and methylomes of normal controls, AD patients, and "AD-in-dish" models were used to identify genetic and epigenetic signatures of AD in FUS. Here we identified changes in gene expression that are specific to the FUS in brains of AD patients. These changes are closely linked to key genes in the AD network. Profiling of the methylome (5mC/5hmC/5fC/5caC) at base resolution identified 5 signature genes (COL2A1, CAPN3, COL14A1, STAT5A, SPOCK3) that exhibit perturbed expression, specifically in the FUS and display altered DNA methylome profiles that are common across AD-associated brain regions. Moreover, we demonstrate proof-of-principle that AD-associated methylome changes in these genes effectively predict the disease prognosis with enhanced sensitivity compared to presently used clinical criteria. CONCLUSIONS: This study identified a set of previously unexplored FUS-specific AD genes and their epigenetic characteristics, which may provide new insights into the molecular pathology of AD, attributing the genetic and epigenetic basis of FUS to AD development.

Epigenetic signatures of methylated DNA cytosine in Alzheimer's disease.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common untreatable form of dementia. Identifying molecular biomarkers that allow early detection remains a key challenge in the diagnosis, treatment, and prognostic evaluation of the disease. Here, we report a novel experimental and analytical model characterizing epigenetic alterations during AD onset and progression. We generated the first integrated base-resolution genome-wide maps of the distribution of 5-methyl-cytosine (5mC), 5-hydroxymethyl-cytosine (5hmC), and 5-formyl/carboxy-cytosine (5fC/caC) in normal and AD neurons. We identified 27 AD region-specific and 39 CpG site-specific epigenetic signatures that were independently validated across our familial and sporadic AD models, and in an independent clinical cohort. Thus, our work establishes a new model and strategy to study the epigenetic alterations underlying AD onset and progression and provides a set of highly reliable AD-specific epigenetic signatures that may have early diagnostic and prognostic implications.

Drug-seeking motivation level in male rats determines offspring susceptibility or resistance to cocaine-seeking behaviour.

Liability to develop drug addiction is heritable, but the precise contribution of non-Mendelian factors is not well understood. Here we separate male rats into addiction-like and non-addiction-like groups, based on their incentive motivation to seek cocaine. We find that the high incentive responding of the F0 generation could be transmitted to F1 and F2 generations. Moreover, the inheritance of high incentive response to cocaine is contingent on high motivation, as it is elicited by voluntary cocaine administration, but not high intake of cocaine itself. We also find DNA methylation differences between sperm of addiction-like and non-addiction-like groups that were maintained from F0 to F1, providing an epigenetic link to transcriptomic changes of addiction-related signalling pathways in the nucleus accumbens of offspring. Our data suggest that highly motivated drug seeking experience may increase vulnerability and/or reduce resistance to drug addiction in descendants.