Project description:DNA methylation is a key epigenetic modification regulating genome organization, stability, and gene expression. Stable DNA methylation critically relies on methyl groups provided through folate-mediated one-carbon (C1) metabolism, yet the origin and regulation of C1 supply remain elusive. Here we demonstrate that photorespiration serves as a major C1 source for DNA methylation in Arabidopsis. We show that C1 from formate, a photorespiratory byproduct, is incorporated into 5-methyl-cytosine via the reductive cytosolic folate pathway. This occurs predominantly during the day, negatively regulating serine utilization as alternative C1 source. Consequently, suppression of photorespiration under elevated CO₂ levels alters the DNA methylation landscape, an effect exacerbated when regulation of C1 metabolism by the formate-dependent pathway is impaired. Thus, our findings link the fundamental metabolic process of photorespiration to epigenetic stability, highlighting how rising atmospheric CO₂ levels can induce DNA methylation changes.
Project description:Current clinical guidelines suggest that breast cancers with low hormone receptor expression (LowHR) in 1% to 10% of tumor cells should be regarded as hormone receptor positive tumors. However, clinical data shows that patients with such tumors have a worse outcome compared to patients with hormone receptor expression above 10 %. Further, gene expression studies suggest that these tumors have a TNBC-like signature similar to triple negative breast cancers (TNBC). The goal of this study was to use DNA methylation-based classification to clarify the status for this infrequent but important patient subgroup. We performed whole genome DNA methylation profiling on 23 LowHR breast cancer specimens, including 13 samples with HER2 amplification and compared our results with a reference breast cancer cohort from The Cancer Genome Atlas. Unsupervised clustering and dimensionality reduction revealed that breast cancers with low hormone receptor expression that lacked HER2 amplification usually clustered with TNBC reference samples (8/10; “LowHR TNBC-like”). In contrast, most specimens with low hormone receptor expression and HER2 amplification grouped with hormone receptor positive cancers (11/13; “LowHR HRpos-like”). We observed highly similar DNA methylation patterns of LowHR TNBC-like samples and true TNBCs with almost no differential methylation. Furthermore, the Ki67 proliferation index of LowHR TNBC-like samples as well as clinical outcome parameters were more similar to TNBCs and differed from LowHR_HRpos-like cases. We here demonstrate that LowHR breast cancer comprises two molecularly distinct groups that can be separated by DNA methylation profiling. More clinical data is required for a definite classification of these tumors, but our data strongly suggests that LowHR TNBC-like samples are molecularly, histologically and clinically closely related to TNBC, while LowHR HRpos-like specimens are closely related to hormone receptor positive tumors.