Biology subjects

Sievers, C.

Publications and source records attributed to Sievers, C..

3 recordsLinked to original sources

bioRxiv2022

Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck.

Cancers often display immune escape, but the mechanisms and potential for reversibility are incompletely understood. Epigenetic dysregulation has been implicated in the immune escape of various cancer types. We have identified the epigenetic modifier SET and MYND-domain containing protein 3 (SMYD3) as a mediator of immune escape in human papilloma virus (HPV)- negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor prognosis and low response to immunotherapy with pembrolizumab, a programmed-death-1 (PD-1) targeting antibody. SMYD3 loss increased the sensitivity of HNSCC cancer cells to IFN-{beta}, resulting in upregulation of type I IFN response and antigen presentation machinery genes. We found that SMYD3 regulates the transcription of Ubiquitin-Like PHD And RING Finger Domain- Containing Protein 1 (UHRF1), a key epigenetic reader of trimethylated lysine 9 on histone H3 (H3K9me3), which binds to H3K9me3-enriched promoters of key immune-related genes and silences their expression. SMYD3 further maintains the repression of immune-related genes through the deposition of H4K20me3 within the gene body regions of these genes. In an anti-PD-1 immune checkpoint resistant syngeneic mouse model of HPV-negative HNSCC, Smyd3 depletion induced influx of CD8+ T-cells, upregulated PD-L1 and MHC class I molecules, and increased sensitivity to anti-PD-1 therapy. SMYD3 overexpression was associated with decreased CD8 T-cell infiltration in tumor samples from patients with HPV-negative HNSCC, and was associated with poor response to pembrolizumab. Overall, these data highlight a previously unreported function of SMYD3 as a master epigenetic regulator of anti-tumor immune response in HPV-negative HNSCC and provide a rationale for translational approaches combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in this devastating disease.

cancer biology↗

bioRxiv2022

Functional connectivity between interoceptive brain regions is associated with distinct health-related domains - a population-based neuroimaging study

Interoception is the sensation, perception, and control of signals from within the body. It has been associated with a broad range of physiological and psychological processes. Further, interoceptive variables are related to specific regions and networks in the human brain. However, it is not clear whether or how these networks relate empirically to different domains of physiological and psychological health at the population level. We analysed a dataset of 19 020 individuals (10 055 females, 8 965 males; mean age: 63 years, age range: 45 - 81 years), who have participated in the UK Biobank Study, a very large scale prospective epidemiological health study. Using canonical correlation analysis (CCA), allowing for the examination of associations between two sets of variables, we related the functional connectome of brain regions implicated in interoception to a selection of non-imaging health and lifestyle related phenotypes, exploring their relationship within modes of population co-variation. In one integrated and data driven analysis, we obtained four statistically significant modes. Modes could be categorised into domains of affect and cardiovascular health, breathing, obesity, and subjective health (all p < 0.0001) and were meaningfully associated with distinct neural circuits. Circuits represent specific neural "fingerprints" of functional domains and set the scope for future studies on the neurobiology of interoceptive involvement in different lifestyle and health related phenotypes. Therefore, our research contributes to the conceptualisation of interoception and may lead to a better understanding of co-morbid conditions in the light of shared interoceptive structures.

neuroscience↗

bioRxiv2019

Encoding Variability: When Pattern Reactivation Does Not Benefit Context Memory

A growing body of evidence suggests that neural pattern reactivation supports successful memory formation across multiple study episodes. Previous studies investigating the beneficial effects of repeated encoding typically presented the same stimuli repeatedly under the same encoding task instructions. In contrast, repeating stimuli in different contexts is associated with superior item memory, but poorer memory for contextual features varying across repetitions. In the present functional magnetic-resonance imaging (fMRI) study, we predicted dissociable mechanisms to underlie the successful formation of context memory when the context in which stimuli are repeated is either held constant or varies at each stimulus presentation. Twenty participants studied names of famous people four times, either in the same task repeatedly, or in four different encoding tasks. This was followed by a surprise recognition memory test, including a source judgement about the encoding task. Behaviourally, different task encoding compared to same task encoding was associated with fewer correct context memory judgements but also better item memory, as reflected in fewer misses. Searchlight representational similarity analysis revealed fMRI pattern reactivation in the posterior cingulate cortex to be higher for correct compared to incorrect source memory judgements in the same task condition, with the opposite pattern being observed in the different task condition. It was concluded that higher levels of pattern reactivation in the posterior cingulate cortex index generalisation across context information, which in turn may improve item memory performance during encoding variability but at the cost of contextual features.

neuroscience↗