Biology subjects

Sledziowska, M.

Publications and source records attributed to Sledziowska, M..

4 recordsLinked to original sources

bioRxiv2021

RPRD Proteins Control Transcription in Human Cells

The regulation of transcription is an essential process that allows the cell to respond to various internal and external signals. RNA Polymerase II (Pol II) activity is controlled by a number of factors which bind to the C-terminal domain (CTD) of its largest subunit, RPB1, and stimulate or suppress RNA synthesis. Here, we demonstrate that CTD-interacting proteins, RPRD2, RPRD1B and RPRD1A act as negative regulators of transcription and their levels inversely correlate with the accumulation of nascent and newly transcribed RNA in human cells. We show that the RPRD proteins form mutually exclusive complexes with Pol II to coordinate their roles in transcriptional control. Our data indicate that RPRD2 exerts the most substantial impact on transcription and has the potential to alter key biological processes including the cellular stress response and cell growth.

molecular biology↗

bioRxiv2021

Non-coding RNAs Associated with Prader-Willi Syndrome Regulate Transcription of Neurodevelopmental Genes in Human Induced Pluripotent Stem Cells

Mutations and aberrant gene expression during cellular differentiation lead to neurodevelopmental disorders such as Prader-Willi syndrome (PWS) which results from the deletion of an imprinted locus on chromosome 15. We analysed chromatin-associated RNA in human induced pluripotent cells (iPSCs) upon depletion of hybrid small nucleolar long non-coding RNAs (sno-lncRNAs) and 5 snoRNA capped and polyadenylated long non-coding RNAs (SPA-lncRNAs) transcribed from the locus deleted in PWS. We found that rapid ablation of these lncRNAs affects transcription of specific gene classes. Downregulated genes contribute to neurodevelopment and neuronal maintenance while genes that are upregulated are predominantly involved in the negative regulation of cellular metabolism and apoptotic processes. Our data revealed the importance of SPA-lncRNAs and sno-lncRNAs in controlling gene expression in iPSCs and provided a platform for synthetic experimental approaches in PWS studies. We conclude that ncRNAs transcribed from the PWS locus are critical regulators of a transcriptional signature important for neuronal differentiation and development.

molecular biology↗

bioRxiv2020

Targeted memory reactivation of a serial reaction time task in SWS, but not REM, preferentially benefits the non-dominant hand

Targeted memory reactivation (TMR) is a technique by which sounds paired with learned information can be used to cue neural reactivation of that information during sleep. While TMR in slow-wave sleep (SWS) has been shown to strengthen procedural memories, it is unclear whether TMR in rapid eye movement (REM) sleep, a state strongly associated with motor consolidation, provides equivalent benefit. Furthermore, it is unclear whether this technique influences dominant and non-dominant hands equally. We applied TMR of a two-handed serial reaction time task (SRTT) during either SWS or REM in thirty-two human right handed adults (sixteen female) to examine the impact of stimulation in each sleep stage on right (dominant) and left hands. While TMR in SWS led to strong benefits in reaction times and sequence-specific skill, equivalent cueing in REM led to no benefit at all, suggesting that reactivation in this sleep stage is not important for the SRTT. Event-related potentials elicited by TMR cues for left and right hand movements differed significantly in REM, but not SWS, showing that these cues are at least processed in REM. Interestingly, TMR benefits were apparent only in the non-dominant hand, potentially due to the weaker performance measured in this hand at the outset. Overall, these findings suggest that memory replay in SWS, but not REM, is important for consolidation of the SRTT, and TMR-cued consolidation is stronger in the non-dominant hand. Significance statementTargeted memory reactivation (TMR) in sleep leads to memory consolidation, but many aspects of this process remain to be understood. We used TMR of a bimanual serial reaction time task to show that behavioural benefit is only observed after stimulation in SWS, even though electrophysiology shows that the TMR cues are processed in REM. Importantly, TMR selectively benefitted the non-dominant hand. These findings suggest that TMR in REM does not benefit this serial reaction time task, and that TMR in SWS preferentially consolidates weaker memory traces relating to the non-dominant hand.

neuroscience↗

bioRxiv2020

Cellular and behavioral characterization of Pcdh19 mutant mice: subtle molecular changes, increased exploratory behavior and an impact of social environment.

Mutations in the X-linked cell adhesion protein PCDH19 lead to seizures, cognitive impairment and other behavioral comorbidities when present in a mosaic pattern. Neither the molecular mechanisms underpinning this disorder, nor the function of PCDH19 itself are well understood. By combining RNA in situ hybridization with immunohistochemistry and analyzing single cell RNAseq datasets, we provide a first account of the subtypes of neurons expressing Pcdh19/PCDH19, both in the mouse and the human cortex. Our quantitative analysis of the Pcdh19 mutant mouse reveals subtle changes in cortical layer composition, with no major alterations of the main axonal tracts. However, Pcdh19 mutant animals, particularly females, display preweaning behavioral changes, including reduced anxiety and increased exploratory behavior. Our experiments also reveal an effect of the social environment on the behavior of wild-type littermates of Pcdh19 mutant mice when compared with wild-type animals not housed with mutants. This is a second case of a mutated X-linked gene encoding a membrane protein expressed in the developing cortex impacting the behavior of co-housed wild-type littermates.

neuroscience↗