Biology subjects

Dahl, J. A.

Publications and source records attributed to Dahl, J. A..

5 recordsLinked to original sources

bioRxiv2025

Major waves of H2A.Z incorporation during mouse oogenesis

Mammalian oocytes and embryos have distinct epigenomes that undergo major transitions essential for transmitting life to the next generation. Here, we provide the first genome-wide maps of the histone variant H2A.Z during six different stages of mouse oogenesis. Utilizing picogram- scale chromatin immunoprecipitation and sequencing (picoChIP-seq), we reveal major waves of H2A.Z incorporation occurring early in growing oocytes. We identify distinct patterns of H2A.Z signal at oocyte-specific, embryo-specific, and constant H2A.Z loci. Late oocyte-specific loci precede reduced formation of lamina associated domains and early replication timing in the maternal compared to the paternal genome of 2-cell embryos. While constant H2A.Z is strongly associated with CpG islands (CGIs) and H3K4me3 near transcription start sites (TSS) of active genes, tens of thousands of oocyte- and embryo-specific H2A.Z incorporation sites exist independently of CGIs and TSSs. These TSS-distal H2A.Z sites are frequently enriched at transposable elements (TEs), and an intriguing inverse relationship exists between H2A.Z and H3K4me3 in low CpG environments, such as MTA and MTB retrotransposons (RTs). The existence of changes in H2A.Z distribution that persist across related developmental stages enable preservation of epigenetic information despite major concurrent changes in H3K4me3, H3K27me3, and DNA methylation. Altogether, this reveals new layers of regulation advancing our understanding of how histone variants contribute to the epigenetic landscape during mammalian oogenesis and preimplantation embryo development.

developmental biology↗

bioRxiv2023

Sex-Specific DNA-Replication In The Early Mammalian Embryo

The timing of mammalian DNA replication is crucial for minimizing errors and is influenced locally by genome usage and chromatin states. However, our understanding of replication timing in the unique environment that exists in newly formed mammalian embryos is limited. Here, we performed genome-wide investigations of replication timing in mouse zygotes and 2-cell embryos. We discovered that zygotes lack a conventional replication timing, but a program emerged in 2-cell embryos. Notably, this program differs from embryonic stem cells and shows asynchrony between the parental genomes. We observed late replication of maternal pericentromeric regions and DNA associated with the nuclear lamina in each parental genome, whereas unexpected early replication occurred in regions with histone marks deposited by Polycomb Repressive Complexes on the maternal chromatin. This atypical and asynchronous replication of the two parental genomes may advance our understanding of replication stress in early human embryos and trigger strategies to reduce errors and aneuploidies.

genomics↗

bioRxiv2021

ALKBH5 regulates somatic cell reprogramming in a phase specific manner

Establishment of the pluripotency regulatory network in somatic cells by introducing four transcriptional factors, (Octamer binding transcription factor 4 (OCT4), SRY (sex determining region Y)-box 2 (SOX2), Kruppel - like factor 4 (KLF4), and cellular-Myelocytomatosis (c-MYC) provides a promising tool for cell-based therapies in regenerative medicine. Still, the mechanisms at play when generating induced pluripotent stem cells from somatic cells is only partly understood. Here we show that the RNA specific N6-methyladenosine (m6A) demethylase ALKBH5 regulates somatic cell reprogramming in a stage specific manner. Knockdown or knockout of Alkbh5 in the early reprogramming phase impairs the reprogramming efficiency by reducing the proliferation rate through arresting the cells at G2/M phase and decreasing the mesenchymal-to-epithelial transition (MET) rate. However, there is no significant change in reprogramming efficiency when Alkbh5 is depleted at the late phase of reprogramming. On the other hand, ALKBH5 overexpression at the earlyreprogramming phase has no significant impact on reprogramming efficiency, while overexpression at the late phase enhances the reprogramming by stabilizing Nanog transcripts resulting in upregulated Nanog expression. Our study provides mechanistic insight into the crucial dynamic role of ALKBH5 in regulating somatic cell reprogramming at the posttranscriptional level.

cell biology↗

bioRxiv2021

Screening bioactive food compounds in honey bees suggests curcumin blocks alcohol-induced damage to longevity and DNA methylation

Various bioactive food compounds may confer health and longevity benefits, possibly through altering or preserving the human epigenome. While bioactive food compounds are widely being marketed as improving health and longevity by counteracting harmful effects of poor nutrition and lifestyle, claimed effects are often not adequately documented. Using the honey bee (Apis mellifera) as a model species, we here employed a multi-step screening approach to investigate seven compounds for effects on lifespan and DNA methylation using ELISA and whole genome bisulfite sequencing (WGBS). A positive longevity effect was detected for valproic acid, isovaleric acid, and cyanocobalamin. For curcumin, we found that lifespan shortening caused by ethanol intake, was restored when curcumin and ethanol were co-administered. Furthermore, we identified region specific DNA methylation changes as a result of ethanol intake. Ethanol specific changes in DNA methylation were fully or partially blocked in honey bees receiving ethanol and curcumin together. Ethanol-affected and curcumin-blocked differentially methylated regions covered genes involved in fertility, temperature regulation and tubulin transport. Our results demonstrate fundamental negative effects of low dose ethanol consumption on lifespan and associated DNA methylation changes and present a proof-of-principle on how longevity and DNA methylation changes can be negated by the bioactive food component curcumin. Our findings provide a fundament for further studies of curcumin in mice and humans and offer an avenue to explore regarding possible prevention of health issues related to alcohol consumption.

genomics↗

bioRxiv2020

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify new regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell-skewed organoid cultures. We found that Lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 represses genes that are normally expressed in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and indeed, we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium towards a reparative state.

developmental biology↗