Publications

The influence of genetic predisposition to Alzheimer’s disease in cognitive decline differs among sex in cognitively unimpaired individuals in the Alzheimer’s <i>continuum</i>

Abstract Background Evidence shows sex differences in cognitive performance in Alzheimer’s disease (AD). However, studies exploring whether genetic predisposition to AD differs in cognition among sex are scarce. We aimed to evaluate whether the influence of AD genetic liability in cognition differs among sex in cognitively unimpaired (CU) individuals in the AD continuum . Method We included 318 CU individuals from the ALFA+ cohort (Table 1). Cognitive change (∼3‐year follow‐up) was measured with a PACC and for individual cognitive domains. Polygenic scores estimating each participant’s genetic predisposition to AD were calculated with (PRS‐AD) and without (PRS‐ADnoAPOE) considering the APOE region (threshold = 5×10‐6). Amyloid positivity (Aβ+) was defined as cerebrospinal fluid (CSF) Aβ42/40&lt;0.0071. Generalized linear models stratified by sex and amyloid status were performed to assess the association between cognitive change and genetic predisposition to AD. Models were corrected by age, years of education, and time between visits. Models were additionally corrected by baseline Jack’s cortical thickness AD signature as a marker of neurodegeneration. Result In Aβ+ women (n = 65), a higher genetic predisposition to AD was associated with steeper memory ( p PRS_AD = 0.04; p PRS_ADnoAPOE = 0.01) and executive function ( p PRS_ADnoAPOE = 0.001) decline after correcting by brain AD signature. In Aβ+ men (n = 44), a higher genetic predisposition to AD was associated with worse follow‐up performance on attention ( p PRS_AD = 0.05, p PRS_ADnoAPOE = 0.04), and results did not remain significant after correcting by brain AD signature (Figure 1). In Aβ‐, genetic predisposition to AD was also associated with executive function decline in women (n = 122) ( p PRS_AD = 0.16, p PRS_ADnoAPOE = 0.02), while Aβ‐ men (n = 87) showed worse follow‐up performance on visual processing ( p PRS_AD = 0.251, p PRS_ADnoAPOE = 0.001). Results remained significant after correcting by brain AD signature (Figure 2). Conclusion Our results showed that genetic predisposition to AD is associated with changes in different cognitive domains in men and women. These findings will contribute to developing precision medicine approaches in AD encompassing sex‐sensitive strategies for prevention.

Data from Epigenetic Inactivation of the Circadian Clock Gene &lt;i&gt;BMAL1&lt;/i&gt; in Hematologic Malignancies

&lt;div&gt;Abstract&lt;p&gt;Disruption of circadian rhythms, daily oscillations in biological processes that are regulated by an endogenous clock, has been linked to tumorigenesis. Normal and malignant tissues often show asynchronies in cell proliferation and metabolic rhythms. Cancer chronotherapy takes biological time into account to improve the therapy. However, alterations of the circadian clock machinery genes have rarely been reported in human cancer. Herein, we show that the &lt;i&gt;BMAL1&lt;/i&gt; gene, a core component of the circadian clock, is transcriptionally silenced by promoter CpG island hypermethylation in hematologic malignancies, such as diffuse large B-cell lymphoma and acute lymphocytic and myeloid leukemias. We also describe how BMAL1 reintroduction in hypermethylated leukemia/lymphoma cells causes growth inhibition in colony assays and nude mice, whereas BMAL1 depletion by RNA interference in unmethylated cells enhances tumor growth. We also show that BMAL1 epigenetic inactivation impairs the characteristic circadian clock expression pattern of genes such as C-MYC, catalase, and p300 in association with a loss of BMAL1 occupancy in their respective promoters. Furthermore, the DNA hypermethylation–associated loss of BMAL1 also prevents the recruitment of its natural partner, the CLOCK protein, to their common targets, further enhancing the perturbed circadian rhythm of the malignant cells. These findings suggest that BMAL1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting the cellular circadian clock. [Cancer Res 2009;69(21):8447–54]&lt;/p&gt;&lt;/div&gt;

Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts

Epigenetic changes through altered DNA methylation have been implicated in critical aspects of tumor progression, and have been extensively studied in a variety of cancer types. In contrast, our current knowledge of the aberrant genomic DNA methylation in tumor-associated fibroblasts (TAFs) or other stromal cells that act as critical coconspirators of tumor progression is very scarce. To address this gap of knowledge, we conducted genome-wide DNA methylation profiling on lung TAFs and paired control fibroblasts (CFs) from non-small cell lung cancer patients using the HumanMethylation450 microarray. We found widespread DNA hypomethylation concomitant with focal gain of DNA methylation in TAFs compared to CFs. The aberrant DNA methylation landscape of TAFs had a global impact on gene expression and a selective impact on the TGF-β pathway. The latter included promoter hypermethylation-associated SMAD3 silencing, which was associated with hyperresponsiveness to exogenous TGF-β1 in terms of contractility and extracellular matrix deposition. In turn, activation of CFs with exogenous TGF-β1 partially mimicked the epigenetic alterations observed in TAFs, suggesting that TGF-β1 may be necessary but not sufficient to elicit such alterations. Moreover, integrated pathway-enrichment analyses of the DNA methylation alterations revealed that a fraction of TAFs may be bone marrow-derived fibrocytes. Finally, survival analyses using DNA methylation and gene expression datasets identified aberrant DNA methylation on the EDARADD promoter sequence as a prognostic factor in non-small cell lung cancer patients. Our findings shed light on the unique origin and molecular alterations underlying the aberrant phenotype of lung TAFs, and identify a stromal biomarker with potential clinical relevance.

lncRNAs and microRNAs with a role in cancer development

Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome

DNA methylation gradiently changes with age and is likely to be involved in aging-related processes with subsequent phenotype changes and increased susceptibility to certain diseases. The Hutchinson-Gilford Progeria (HGP) and Werner Syndrome (WS) are two premature aging diseases showing features of common natural aging early in life. Mutations in the LMNA and WRN genes were associated to disease onset; however, for a subset of patients the underlying causative mechanisms remain elusive. We aimed to evaluate the role of epigenetic alteration on premature aging diseases by performing comprehensive DNA methylation profiling of HGP and WS patients. We observed profound changes in the DNA methylation landscapes of WRN and LMNA mutant patients, which were narrowed down to a set of aging related genes and processes. Although of low overall variance, non-mutant patients revealed differential DNA methylation at distinct loci. Hence, we propose DNA methylation to have an impact on premature aging diseases.

Additional file 8 of Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer

Supplementary Material 8

The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion

Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth.We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-κB p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation.Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts.

Extending MeCP2 interactome: canonical nucleosomal histones interact with MeCP2

Abstract MeCP2 is a general regulator of transcription involved in the repression/activation of genes depending on the local epigenetic context. It acts as a chromatin regulator and binds with exquisite specificity to gene promoters. The set of epigenetic marks recognized by MeCP2 has been already established (mainly, cytosine modifications in CpG and CpA), as well as many of the constituents of its interactome. We unveil a new set of interactions for MeCP2 with the four canonical nucleosomal histones. MeCP2 interacts with high affinity with H2A, H2B, H3 and H4. In addition, Rett syndrome associated mutations in MeCP2 and histone epigenetic marks modulate these interactions. Given the abundance and the structural/functional relevance of histones and their involvement in epigenetic regulation, this new set of interactions and its modulating elements provide a new addition to the ‘alphabet’ for this epigenetic reader.

Additional file 6: of Walking pathways with positive feedback loops reveal DNA methylation biomarkers of colorectal cancer

Table S11. Table of pairwise Pearson correlations between CpG methylation values of pre-selected markers. (XLSX 63â kb)

DNA methylation in stem cell renewal and multipotency

Owing to their potential for differentiation into multiple cell types, multipotent stem cells extracted from many adult tissues are an attractive stem cell resource for the replacement of damaged tissues in regenerative medicine. The requirements for cellular differentiation of an adult stem cell are a loss of proliferation potential and a gain of cell-type identity. These processes could be restricted by epigenetic modifications that prevent the risks of lineage-unrelated gene expression or the undifferentiated features of stem cells in adult somatic cells. In this review, we focus on the role of DNA methylation in controlling the transcriptional activity of genes important for self-renewal, the dynamism of CpG methylation of tissue-specific genes during several differentiation programs, and whether the multilineage potential of adult stem cells could be imposed early in the original precursor stem cells through CpG methylation. Additionally, we draw attention to the role of DNA methylation in adult stem cell differentiation by reviewing the reports on spontaneous differentiation after treatment with demethylating agents and by considering the evidence provided by reprogramming of somatic cells into undifferentiated cells (that is, somatic nuclear transfer or generation of induced pluripotent cells). It is clear from the evidence that DNA methylation is necessary for controlling stem cell proliferation and differentiation, but their exact contribution in each lineage program is still unclear. As a consequence, in a clinical setting, caution should be exerted before employing adult stem cells or their derivatives in regenerative medicine and appropriate tests should be applied to ensure the integrity of the genome and epigenome.

Supplementary Figure 3 from A Novel Epigenetic Signature for Early Diagnosis in Lung Cancer

&lt;p&gt;Differentially methylated levels in neighboring CpGs on the selected candidate genes.&lt;/p&gt;

Table S2 from ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms

&lt;p&gt;Panel of antibodies used in flow cytometry experiments.&lt;/p&gt;

Rolling the Dice to Discover the Role of DICER in Tumorigenesis

Walking pathways with positive feedback loops reveal DNA methylation

What drives demand for redistribution? An empirical analysis of other-regarding and self-insurance motives

Figure S17 from ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms

&lt;p&gt;Sensitivity to ibrutinib was evaluated by MTT assay (72h). Karpas1718 parental (top) or resistant (bottom) were exposed to 100nM decitabine (A), 5µM tazemetostat (B), or DMSO (control, black) given concomitantly (continuous lines) or 72 hours before ibrutinib (pre DMSO in dashed black or pre decitabine/tazemetostat in dashed red). Error bars correspond to standard deviation of the mean. Data derived from two independent experiments. Statistically significant differences were evaluated by moderated t-test comparing each treatment to control (DMSO).&lt;/p&gt;

supplementary figure 1 from CD137 (4-1BB) Costimulation Modifies DNA Methylation in CD8&lt;sup&gt;+&lt;/sup&gt; T Cell–Relevant Genes

&lt;p&gt;No change in memory naive proportions and their DNA methylation in relevant genes&lt;/p&gt;

Figure S5 from ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms

&lt;p&gt;Parental (green) and resistant (orange) levels of DNA promoter methylation (A) and gene expression (RNA-seq, B) of DUSP4, and p-ERK upon 1µM of idelalisib (Flow cytometry).&lt;/p&gt;