Biology subjects

Kemper, K.

Publications and source records attributed to Kemper, K..

6 recordsLinked to original sources

bioRxiv2025

Inhibition of lysine deacetylase activity impacts formation of the vitamin D receptor activation complex.

The vitamin D endocrine system is responsible for the regulation of many biological processes including bone metabolism, calcium homeostasis, cell proliferation and cell differentiation. Alterations to the vitamin D signaling pathway are associated with several diseases including bone diseases, diabetes, cardiovascular diseases, autoimmune diseases, and cancer. Vitamin D precursors are obtained through diet or synthesized in the skin and must be further chemically modified to become the biologically active hormone, calcitriol. Calcitriol binds to the vitamin D receptor (VDR), a member of the nuclear hormone receptor (NHR) superfamily. VDR forms a heterodimer with retinoid X receptor (RXR) and together they bind to promoters containing vitamin D response elements (VDREs) to activate transcription of target genes. Other NHRs have been shown to accept post-translational modifications that can either increase or decrease their transcriptional output through alterations in protein-protein or protein-DNA interactions. We have generated evidence that two lysines on VDR may be targets of post-translational modifications, and alterations to lysine deacetylase activity will impact VDR transcriptional output through changes in co-activator and co-repressor binding. Together, these data suggest a novel way for the cell to modulate the response of VDR to available vitamin D.

molecular biology↗

bioRxiv2024

Somatic gonad morphogenesis in C. elegans requires the heterochronic pathway acting through HBL-1

Characteristically, the heterochronic genes control the stage-specific timing of developmental events throughout the developing Caenorhaditis elegans larva while gonad development occurs mostly normally. In a few cases, some timing regulators lead to detectable variations in gonad development with little to no effect on fertility. We found that a double mutant of a lin-28 null allele and hbl-1 hypomorphic allele results in a catastrophic failure of gonad morphogenesis resulting in sterility. This defect includes a high-penetrance disruption of normal gonad arm migration as well as frequent absence of one or both spermathecae. We demonstrate that the abnormal gonad morphology and novel sterility phenotype is ultimately due to loss of hbl-1 activity in larval development. The mechanism of how lin-28 positively influences hbl-1 activity is unresolved. We demonstrate a direct interaction between the RNA-binding protein LIN- 28 and the 5UTR of lin-46, and in turn, a direct interaction between LIN-46 and two zinc fingers of HBL-1. Nevertheless, our genetic analysis indicates that lin-46 accounts for only part of lin-28s regulation of hbl-1 and that some portion of lin-28s effect is independent of lin-46.

molecular biology↗

bioRxiv2020

PREDICTIVE IMMUNE CHECKPOINT BLOCKADE CLASSIFIERS DISTINGUISHING MONO- VERSUS COMBINATION THERAPY REQUIREMENT

Although high clinical response rates are seen for immune checkpoint blockade (ICB) treatment of metastatic melanomas, both intrinsic and acquired ICB resistance remain considerable clinical challenges1. Combination ICB (anti-PD-1 + anti-CTLA-4) shows improved patient benefit2-5, but is associated with severe adverse events and exceedingly high cost. Therefore, there is a dire need to stratify individual patients for their likelihood of responding to either anti-PD-1 or anti-CTLA-4 monotherapy, or the combination. Since it is conceivable that ICB responses are influenced by both tumor cell-intrinsic and -extrinsic factors6-9, we hypothesized that a predictive genetic classifier ought to mirror both these features. In a panel of patient-derived melanoma xenografts10 (PDX), we noted that cells derived from the human tumor microenvironment (TME) that were co-grafted with the tumor cells were naturally replaced by murine cells after the first passage. Taking advantage of the XenofilteR11 algorithm we recently developed to deconvolute human from murine RNA sequence reads from PDX10, we obtained curated human melanoma tumor cell RNA reads. These expression signals were computationally subtracted from the total RNA profiles in bulk (tumor cell + TME) melanomas from patients. We thus derived one genetic signature that is purely tumor cell-intrinsic ("InTumor"), and one that comprises tumor cell-extrinsic RNA profiles ("ExTumor"). Here we report that the InTumor signature predicts patient response to anti-PD-1, but not anti-CTLA-4 treatment. This was validated in melanoma PDX and cell lines, which confirmed that InTumorLO tumors were effectively eliminated by adoptive cell transfer of T-Cell Receptor (TCR)-matched cytotoxic T cells, whereas InTumorHI melanomas were refractory and grew out as fast as tumors challenged with unmatched T cells. In contrast, the ExTumor signature predicts patient response to anti-CTLA-4 but not anti-PD-1. Most importantly, we used the InTumor and ExTumor signatures in conjunction to generate an ICB response quadrant, which predicts clinical benefit for five independent melanoma patient cohorts treated with either mono- or combination ICB. Specifically, these signatures enable identification of patients who have a much higher chance of responding to the combination treatment than to either monotherapy (p < 0.05), as well as patients who are likely to experience little benefit from receiving anti-CTLA-4 on top of anti-PD-1 (p < 0.05). These signatures may be clinically exploited to distinguish patients who need combined PD-1 + CTLA-4 blockade from those who are likely to benefit from either anti-CTLA-4 or anti-PD-1 monotherapy.

cancer biology↗

bioRxiv2018

The effect of X-linked dosage compensation on complex trait variation

Quantitative genetics theory predicts that X-chromosome dosage compensation between sexes will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of dosage compensation in complex trait variation in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and in 1,600 gene expression traits from a sample of 2,000 individuals as well as across-tissue gene expression from the GTEx resource. We find, on average, twice as much genetic variation for complex traits due to X-linked loci in males compared to females, consistent with a negligible effect of predicted escape from X-inactivation on complex trait variation across traits and also detect biologically relevant X-linked heterogeneity between the sexes for a number of complex traits.

genetics↗

bioRxiv2018

Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood

Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes associated with brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top associated cis-expression (cis-eQTLs or cis-mQTLs) between brain and blood for genes expressed (or CpG sites methylated) in both tissues, while accounting for errors in their estimated effects (rb). Using publicly available data (n = 72 to l,366), we find that the genetic effects of cis-eQTLs (PeQTL < 5x10-8) or mQTLs (PmQTL < 1x10-10) are highly correlated between independent brain and blood samples ([Formula] with SE = 0.015 for cis-eQTL and [Formula] with SE = 0.006 for cis-mQTLs). Using meta-analyzed brain eQTL/mQTL data (n = 526 to 1,194), we identify 61 genes and 167 DNA methylation (DNAm) sites associated with 4 brain-related traits and disorders. Most of these associations are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = l,980 to 14,115). We further find that cis-eQTLs with tissue-specific effects are approximately uniformly distributed across all the functional annotation categories, and that mean difference in gene expression level between brain and blood is almost independent of the difference in the corresponding cis-eQTL effect. Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL or cis-mQTL data with large sample sizes.

genetics↗

bioRxiv2017

A screen for combination therapies in BRAF/NRAS wild type melanoma identifies nilotinib plus MEK inhibitor as a synergistic combination

Despite recent therapeutic advances in the management of BRAFV600-mutant melanoma, there is still a compelling need for more effective treatments for patients who developed BRAF/NRAS wild type disease. Since the activity of single targeted agents is limited by innate and acquired resistance, we performed a high-throughput drug screen using 180 drug combinations to generate over 18,000 viability curves, with the aim of identifying agents that synergise to kill BRAF/NRAS wild type melanoma cells. From this screen we observed strong synergy between the tyrosine kinase inhibitor nilotinib and MEK inhibitors and validated this combination in an independent cell line collection. We found that AXL expression was associated with synergy to the nilotinib/MEK inhibitor combination, and that both drugs work in concert to suppress pERK. This finding was supported by genome-wide CRISPR screening which revealed that resistance mechanisms converge on regulators of the MAPK pathway. Finally, we validated the synergy of nilotinib/trametinib combination in vivo using patient-derived xenografts. Our results indicate that a nilotinib/MEK inhibitor combination may represent an effective therapy in BRAF/NRAS wild type melanoma patients.

cancer biology↗