Biology subjects

Saetrom, P.

Publications and source records attributed to Saetrom, P..

9 recordsLinked to original sources

bioRxiv2025

Pyranges v1: a Python framework for ultrafast sequence interval operations

Sequence interval algebra is key to modern bioinformatics. Pyranges v1 offers a Python Pandas-based interface to a comprehensive palette of Rust-powered operations (e.g., overlap, count, slice intervals), enabling the intuitive development of efficient pipelines for diverse sequence data, including gene annotations, mapped reads, and protein domains. Pyranges is faster, consumes less memory, and offers more functionalities than alternative tools including BEDTools, emerging as an innovative one-stop shop for omics analysis.

bioinformatics↗

bioRxiv2023

Loss of alkyladenine DNA glycosylase alters gene expression in the developing mouse brain and leads to reduced anxiety and improved memory

Neurodevelopment is a tightly coordinated process, during which the genome is exposed to spectra of endogenous agents at different stages of differentiation. Emerging evidence indicates that DNA damage is an important feature of developing brain, tightly linked to gene expression and neuronal activity. Some of the most frequent DNA damage includes changes to DNA bases, which are recognized by DNA glycosylases and repaired through base excision repair (BER) pathway. The only mammalian DNA glycosylase able to remove frequent alkylated DNA based is alkyladenine DNA glycosylase (Aag, aka Mpg). We recently demonstrated that, besides its role in DNA repair, AAG affects expression of neurodevelopmental genes in human cells. Aag was further proposed to act as reader of epigenetic marks, including 5-hydroxymethylcytosine (5hmC), in the mouse brain. Despite the potential Aag involvement in the key brain processes, the impact of Aag loss on developing brain remains unknown. Here, by using Aag knockout (Aag-/-) mice, we show that Aag absence leads to reduced DNA break levels, evident in lowered number of {gamma}H2AX foci in postnatal day 5 (P5) hippocampi. This is accompanied by changes in 5hmC signal intensity in different hippocampal regions. Transcriptome analysis of hippocampi and prefrontal cortex, at different developmental stages, indicates that lack of Aag alters gene expression, primarily of genes involved in regulation of response to stress. Across all developmental stages tested aldehyde dehydrogenase 2 (Aldh2) emerged as one of the most prominent genes deregulated in Aag-dependent manner. In line with the changes in hippocampal DNA damage levels and the gene expression, adult Aag-/- mice exhibit altered behavior, evident in decreased anxiety levels determined in the Elevated Zero Maze and increased alternations in the Elevated T Maze tests. Taken together these results suggests that Aag has functions in modulation of genome dynamics during brain development, important for animal behavior. HighlightsO_LIAag loss results in reduced DNA damage signal in developing hippocampus; C_LIO_LI5hmC signal intensity is perturbed in hippocampal regions of Aag-/- mice; C_LIO_LIGene expression is altered in Aag-/- hippocampus and prefrontal cortex; C_LIO_LIAag represses Aldh2 expression; C_LIO_LIAag-/- mice have reduced anxiety and improved memory. C_LI

molecular biology↗

bioRxiv2022

Persistence of Cajal-Retzius cells in the postnatal hippocampus is required for development of dendritic spines of CA1 pyramidal cells

Cajal-Retzius (CR) cells are a transient type of neuron that populate the postnatal hippocampus. The role of transient cell types and circuits have been vastly addressed in neocortical regions, but poorly studied in the hippocampus. To understand how CR cells persistence influences the maturation of hippocampal circuits, we specifically ablated CR cells from the postnatal hippocampus. Our results highlighted layer-specific effects on dendritic spines and synaptic-related genes and revealed a critical role of CR cells in the establishment of the hippocampal network.

neuroscience↗

bioRxiv2021

The G2-phase enriched lncRNA SNHG26 is necessary for proper cell cycle progression and proliferation

Long noncoding RNAs (lncRNAs) are involved in the regulation of cell cycle, although only a few have been functionally characterized. By combining RNA sequencing and ChIP sequencing of cell cycle synchronized HaCaT cells we have previously identified lncRNAs highly enriched for cell cycle functions. Based on a cyclic expression profile and an overall high correlation to histone 3 lysine 4 trimethylation (H3K4me3) and RNA polymerase II (Pol II) signals, the lncRNA SNHG26 was identified as a top candidate. In the present study we report that downregulation of SNHG26 affects mitochondrial stress, proliferation, cell cycle phase distribution, and gene expression in cis- and in trans, and that this effect is reversed by upregulation of SNHG26. We also find that the effect on cell cycle phase distribution is cell type specific and stable over time. Results indicate an oncogenic role of SNHG26, possibly by affecting cell cycle progression through the regulation of downstream MYC-responsive genes.

molecular biology↗

bioRxiv2021

Joint changes in RNA, RNA polymerase II, and promoter activity through the cell cycle identify non-coding RNAs involved in proliferation

Proper regulation of the cell cycle is necessary for normal growth and development of all organisms. Conversely, altered cell cycle regulation often underlies proliferative diseases such as cancer. Long non-coding RNAs (lncRNAs) are recognized as important regulators of gene expression and are often found dysregulated in diseases, including cancers. However, identifying lncRNAs with cell cycle functions is challenging due to their often low and cell-type specific expression. We present a highly effective method that analyses changes in promoter activity, transcription, and RNA levels for identifying genes enriched for cell cycle functions. Specifically, by combining RNA sequencing with ChIP sequencing through the cell cycle of synchronized human keratinocytes, we identified 1009 genes with cell cycle-dependent expression and correlated changes in RNA polymerase II occupancy or promoter activity as measured by histone 3 lysine 4 trimethylation (H3K4me3). These genes were highly enriched for genes with known cell cycle functions and included 59 lncRNAs. We selected four of these lncRNAs - AC005682.5, RP11-132A1.4, ZFAS1, and EPB41L4A-AS1 - for further experimental validation and found that knockdown of each of the four lncRNAs affected cell cycle phase distributions and reduced proliferation in multiple cell lines. These results show that many genes with cell cycle functions have concomitant cell-cycle dependent changes in promoter activity, transcription, and RNA levels and support that our multi-omics method is well suited for identifying lncRNAs involved in the cell cycle.

molecular biology↗

bioRxiv2021

The lncRNA EPB41L4A-AS1 regulates gene expression in the nucleus and exerts cell type-dependent effects on cell cycle progression

The long non-coding RNA (lncRNA) EPB41L4A-AS1 is aberrantly expressed in various cancers and has been reported to be involved in metabolic reprogramming and as a repressor of the Warburg effect. Although the biological relevance of EPB41L4A-AS1 is evident, its functional role seems to vary depending on cell type and state of disease. By combining RNA sequencing and ChIP sequencing of cell cycle synchronized HaCaT cells we previously identified EPB41L4A-AS1 to be one of 59 lncRNAs with potential cell cycle functions. Here, we demonstrate that EPB41L4A-AS1 exists as bright foci and regulates gene expression in the nucleus in both cis and trans. Specifically, we find that EPB41L4A-AS1 positively regulates its sense overlapping gene EPB41L4A and influences expression of hundreds of other genes, including genes involved in cell proliferation. Finally, we show that EPB41L4A-AS1 affects cell cycle phase distribution, though these effects vary between cell types.

molecular biology↗

bioRxiv2021

NEIL1 and NEIL2 DNA glycosylases regulate anxiety and learning in a cooperative manner

Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases alter cognition in mice, the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in single and double knock-out mouse models. Neil1-/-Neil2-/- mice displayed hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels were comparable between genotypes, no mutator phenotype was found. Impaired canonical repair was thus not the cause of altered behavior. Electrophysiology indicated reduced stratum oriens afferents in the hippocampal CA1 region in Neil1-/-Neil2-/-. Within CA1, NEIL1 and NEIL2 jointly regulated transcription in genes relevant for synaptic function. Thus, we postulate a cooperative function of NEIL1 and NEIL2 in genome regulation beyond canonical BER modulating memory formation and anxiety.

molecular biology↗

bioRxiv2019

Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression

Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG; aka MPG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here we show that AAG binds to chromatin and forms complex with active RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation. Importantly, at co-regulated genes aberrantly methylated bases accumulate towards 3end, in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide novel insights to maintaining genome stability in actively transcribing chromatin, and reveal roles of aberrantly methylated bases in regulation of gene expression.

molecular biology↗

bioRxiv2019

PyRanges: efficient comparison of genomic intervals in Python

SummaryComplex genomic analyses often use sequences of simple set operations like intersection, overlap, and nearest on genomic intervals. These operations, coupled with some custom programming, allow a wide range of analyses to be performed. To this end, we have written PyRanges, a data structure for representing and manipulating genomic intervals and their associated data in Python. Run single-threaded on binary set operations, PyRanges is in median 2.3-9.6 times faster than the popular R GenomicRanges library and is equally memory efficient; run multi-threaded on 8 cores, our library is up to 123 times faster. PyRanges is therefore ideally suited both for individual analyses and as a foundation for future genomic libraries in Python.\n\nAvailabilityPyRanges is available open-source under the MIT license at https://github.com/biocore-NTNU/pyranges and documentation exists at https://biocore-NTNU.github.io/pyranges/\n\nContactendrebak85@gmail.com\n\nSupplementary informationSupplementary data are available.

genomics↗