Biology subjects

Vertino, P. M.

Publications and source records attributed to Vertino, P. M..

7 recordsLinked to original sources

bioRxiv2026

KMT5C-H4K20me3 drives changes in epigenetic landscape independent of H3K9me3

Histone H4 lysine 20 trimethylation (H4K20me3) is a histone modification that is critical in maintaining genome integrity. Dysregulation of H4K20me3 and KMT5C, the major methyltransferase for H4K20me3, occurs commonly in multiple types of cancer but the mechanisms surrounding how they contribute to shaping the epigenomic landscape remains unclear. Here, we show that KMT5C is involved in non-canonical deposition of H4K20me3, independent of H3K9me3, which was previously recognized as a prerequisite for H4K20me3. This novel subtype of H4K20me3 lacks canonical repressive epigenetic signatures and instead overlaps with multiple activating marks. These activating modifications likely contribute to the dynamic changes in transcript levels upon loss of H4K20me3. The mechanism involved in recruiting KMT5C to these loci is independent of HP1, the factor reported to be involved in recruitment of KMT5C to heterochromatin marked with H3K9me3. Instead, biochemical analyses revealed ZNF280C to be a novel interacting partner of KMT5C, with ZNF280C localizing specifically at H3K9me3-/H4K20me3+ sites. Together, these results suggest a novel, non-canonical function of KMT5C-H4K20me3 that protects vulnerable regions of the genome from uncontrolled expression.

genomics↗

bioRxiv2025

MYC and Epithelial to Mesenchymal Transition (EMT) Independently Predict Circadian Rhythm Disruption in Lung Adenocarcinoma

The molecular circadian clock is known to be disrupted in lung adenocarcinoma, and its disruption is pro-tumorigenic in mouse models of this disease. However, the determinants of disruption of the molecular clock in human cancer are not clear. We hypothesized that derangement in expression of specific circadian clock genes or elevated MYC expression could correlate with circadian disruption in human tumors, and used Clock Correlation Distance (CCD) to compare clock order and strength in tumors based on the expression of these genes. While the expression of individual circadian genes did not consistently correlate with disruption, tumors with the highest expression of MYC or high MYC pathway activation had significantly disrupted rhythms compared to those with lower MYC. Unexpectedly, a subset of tumors with very low levels of MYC, below that found in normal lung, also showed disruption of circadian rhythms, prompting us to explore novel determinants of disruption in these tumors. We found that expression of programs associated with epithelial to mesenchymal Transition (EMT) and TGF-{beta} signaling were enriched in tumors with the lowest MYC expression, and that, surprisingly, those tumors with a mesenchymal expression pattern had more ordered (stronger) rhythms. To directly test this correlation between cell state and rhythms, we exposed lung adenocarcinoma cells to TGF-{beta} to induce EMT. TGF-{beta} induced a quasi-mesenchymal phenotype and caused a significant increase in the amplitude of oscillations in these cells. Together, our data show that MYC expression, pathway activation, and a mesenchymal cell state are both independent determinants of circadian status in lung adenocarcinoma.

cancer biology↗

bioRxiv2025

CUT&Tag Identifies Repetitive Genomic Loci that are Excluded from ChIP Assays

Determining the genomic localization of chromatin features is an essential aspect of investigating gene expression control, and ChIP-Seq has long been the gold standard technique for interrogating chromatin landscapes. Recently, the development of alternative methods, such as CUT&Tag, have provided researchers with alternative strategies that eliminate the need for chromatin purification, and allow for in situ investigation of histone modifications and chromatin bound factors. Mindful of technical differences, we set out to investigate whether distinct chromatin modifications were equally compatible with these different chromatin interrogation techniques. We found that ChIP-Seq and CUT&Tag performed similarly for modifications known to reside at gene regulatory regions, such as promoters and enhancers, but major differences were observed when we assessed enrichment over heterochromatin-associated loci. Unlike ChIP-Seq, CUT&Tag detects robust levels of H3K9me3 at a substantial number of repetitive elements, with especially high sensitivity over evolutionarily young retrotransposons. IAPEz-int elements for example, exhibited underrepresentation in mouse ChIP-Seq datasets but strong enrichment using CUT&Tag. Additionally, we identified several euchromatin-associated proteins that co-purify with repetitive loci and are similarly depleted when applying ChIP-based methods. This study reveals that our current knowledge of chromatin states across the heterochromatin portions of the mammalian genome is extensively incomplete, largely due to limitations of ChIP-Seq. We also demonstrate that newer in situ chromatin fragmentation-based techniques, such as CUT&Tag and CUT&RUN, are more suitable for studying chromatin modifications over repetitive elements and retrotransposons. HighlightsIn situ fragmentation overcomes biases produced by ChIP-Seq. Heterochromatic regions of the genome are lost to the insoluble pellet during ChIP-Seq. CUT&Tag allows for mapping chromatin features at young repetitive elements. Euchromatin-associated regulatory factors co-purify with insoluble heterochromatin.

genomics↗

bioRxiv2024

The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion

The mechanisms that regulate cancer dormancy remain poorly understood. Using a mouse model of resectable pancreatic adenocarcinoma (PDAC), we identified Dec2 as a gene that was upregulated in metastatic dormant tumor cells. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism as the survival benefit was abrogated in immunodeficient conditions. Dec2 promoted immune evasion by repressing multiple components of the MHC-I dependent antigen presentation pathway in tumor cells. Dec2 is a regulator of circadian rhythms, and we found several components of the antigen presentation pathway oscillated in a circadian manner that was lost upon deletion of Dec2. Moreover, T-cell mediated tumor cell killing varied depending on the time of day. We suggest that lowered MHC-I presentation of antigens during rest phase is a natural effect of the circadian clock, which is exploited by Dec2-overexpressing pancreatic tumors to evade the immune system.

cancer biology↗

bioRxiv2022

Retrotransposons facilitates tissue specific horizontal Transfer of circulating tumor DNA

A variety of organisms have been shown to have altered physiology or developed pathology due to gene transfer, but mammals have never been shown to do so. Here, we show that circulating tumor DNA (ct) can promote cell-specific horizontal gene transfer (HGT) between human cancer cells and explain the mechanisms behind this phenomenon. Once ctDNA enters the host cell, it migrates to the nucleus and integrates into the cells genome, thereby transferring its genetic information. We determine that retrotransposons of the ERVL, SINE, and LINE families are necessary for cell targeting and the integration of ctDNA into host DNA. Using chemically synthesized retrotransposons, we found that AluSp and MER11C reproduced multiple myelomas (MM) ctDNAs cell targeting and integration into MM cells. We also discovered that ctDNA might, as a result of HGT, influence the treatment response of multiple myeloma and pancreatic cancer models. Overall, this is the first study to show that retrotransposon-directed HGT can promote genetic material transfer in cancer. There is, however, a broader impact of our findings than just cancer since cell-free DNA has also been found in physiological and other pathological conditions as well. Furthermore, with the discovery of transposons-mediated tissue-specific targeting, a new avenue for the delivery of genes and therapies will emerge.

cancer biology↗

bioRxiv2021

Chromatin Patterns Distinguish Breast Tumor Subtypes and Disease Progression in Association with ANP32E levels

Despite highly advanced diagnosis and treatment strategies, breast cancer patient outcomes vary extensively, even among individuals with the same diagnosis. Thus, a better understanding of the unique molecular characteristics that underlie tumor trajectories and responses to therapy remains a central goal. We report that chromatin patterns represent an important characteristic, capable of stratifying tumor identity and progression. We find that patterns of chromatin accessibility can be classified into 3 major groups, representing Basal-like tumors, hormone receptor (HR)-expressing tumors, and invasive lobular Luminal-A tumors. Major chromatin differences occur throughout the genome at motifs for the transcription factor FOXA1 in HR-positive tumors, and motifs for SOX9 in Basal-like tumors. A large portion of lobular Luminal-A tumors display a chromatin signature defined by accessibility at FOXA1 binding motifs, distinguishing them from others within this subtype. Expression of the histone chaperone ANP32E is inversely correlated with tumor progression and chromatin accessibility at FOXA1 binding sites. Tumors with high levels of ANP32E exhibit an immune response and proliferative gene expression signature, whereas tumors with low ANP32E levels appear programmed for differentiation. Our results indicate that ANP32E may function through chromatin state regulation to control breast cancer differentiation and tumor plasticity.

cancer biology↗

bioRxiv2018

Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high-risk. To better understand and identify high-risk myeloma, we analyzed the translocation landscape of 826 newly-diagnosed patients by whole genome sequencing as part of the CoMMpass study. Translocations at the IgL locus were present in 10% of myeloma patients, and corresponded with poor prognosis. Importantly, 70% of IgL translocations co-occurred with hyperdiploid disease, a marker of standard risk, which is routinely diagnosed clinically whereas IgL-translocations are not. Thus, it is likely that the majority of IgL-translocated myeloma is being misclassified. The IgL enhancer is among the strongest in myeloma cells, indicating it can robustly drive oncogene expression when translocated. Consistent with this, IgL-translocated patients failed to benefit from immunomodulatory imide drugs (IMiDs), which target the lymphocyte-specific transcription factor Ikaros. These data implicate the IgL enhancer as resistant to IMiD-inhibition, and when translocated, as a driver of poor prognosis.

genomics↗