Biology subjects

Roberts, S. G. E.

Publications and source records attributed to Roberts, S. G. E..

3 recordsLinked to original sources

bioRxiv2022

The BASP1 transcriptional repressor modifies chromatin through lipid-dependent and lipid-independent mechanisms

The transcriptional corepressor BASP1 requires N-terminal myristoylation for its activity and functions through interactions with nuclear lipids. Here we determine the role of BASP1 lipidation in histone modification and the modulation of chromatin accessibility. We find that the removal of the active histone modifications H3K9ac and H3K4me3 by BASP1 requires the N-terminal myristoylation of BASP1. In contrast, the placement of the repressive histone modification, H3K27me3, by BASP1 does require BASP1 lipidation. RNA-seq and ATAC-seq analysis finds that BASP1 regulates the activity of multiple transcription factors and induces extensive changes in chromatin accessibility. We find that [~]50% of BASP1 target genes show lipidation-dependent chromatin compaction and transcriptional repression. Our results suggest that BASP1 elicits both lipid-dependent and lipid-independent functions in histone modification and transcriptional repression. In accordance with this, we find that the tumor suppressor activity of BASP1 is also partially dependent on its myristoylation.

biochemistry↗

bioRxiv2021

Nuclear cholesterol is required for transcriptional repression by BASP1

Lipids are present within the cell nucleus where they engage with factors involved in gene regulation. Cholesterol associates with chromatin in vivo and stimulates nucleosome packing in-vitro, but its effects on specific transcriptional responses are not clear. Here we show that the lipidated WT1 transcriptional corepressor, BASP1, interacts with cholesterol in the cell nucleus through a conserved cholesterol interaction motif. We demonstrate that BASP1 directly recruits cholesterol to the promoter region of WT1 target genes. Mutation of BASP1 to ablate its interaction with cholesterol or the treatment of cells with drugs that block cholesterol biosynthesis inhibit the transcriptional repressor function of BASP1. We find that the BASP1-cholesterol interaction is required for BASP1-dependent chromatin remodelling and the direction of transcription programs that control cell differentiation. Our study uncovers a mechanism for gene-specific targeting of cholesterol where it is required to mediate transcriptional repression. SignificanceCholesterol is present within the cell nucleus where it associates with chromatin but to date, a direct role for cholesterol in nuclear processes has not been identified. We demonstrate that the transcriptional repressor BASP1 directly interacts with cholesterol within the cell nucleus through a consensus cholesterol interaction motif. BASP1 recruits cholesterol to the promoter region of target genes where it is required to mediate chromatin remodelling and transcriptional repression. Our work demonstrates that nuclear cholesterol plays a direct role in transcriptional regulation.

biochemistry↗

bioRxiv2019

Differential effects of diet and weight on taste responses in diet-induced obese mice

The ever growing obesity epidemic has created a need to develop a better understanding of the underlying mechanisms responsible for this condition. Appetite and consumption are directly influenced by the taste system which determines if potential food items will be ingested or rejected. While previous studies have reported that obese individuals have reduced taste perception, the relationship between these processes is still poorly understood. Earlier work has demonstrated that diet-induced obesity (DIO) directly impairs taste responses, particularly for sweet stimuli. These deficits occurred in the cells located in the oral cavity as well as in the behavioral responses. However, it is not clear if these changes to the taste system are due to obesity or to the high fat diet exposure. The goal of the current study was to determine if diet or excess weight is responsible for the DIO induced taste deficits. Using a combination of live cell imaging, brief-access licking, immunohistochemistry and real-time PCR, we have found that diet and weight gain can each selectivity affect taste. Follow up experiments determined that two key signaling proteins, gustducin and phospholipase C{beta}2, are significantly reduced in the high fat diet without weight gain and obese mice, identifying a potential mechanism for the reduced taste responsiveness to some stimuli. Our data indicate that the relationship between obesity and taste is complex and reveal that for some stimuli, diet alone can cause taste deficits, even without the onset of obesity.

neuroscience↗