Biology subjects

Fleishaker, M.

Publications and source records attributed to Fleishaker, M..

3 recordsLinked to original sources

bioRxiv2026

The TET-dependent DNA demethylation pathway is the driving force of hematopoiesis

A complex network of signaling cascades regulates the differentiation of hematopoietic stem and progenitor cells (HSPCs) into mature blood cells during hematopoiesis. We demonstrated that DNA demethylation driven by Ten-Eleven Translocation (TET) enzymes controls the activity of multiple of these signaling cascades. This occurs because dozens of genes, essential for the specification (e.g., Gata1, Tcf7, Bcl11b, Pou2af1) and maturation (e.g., TCR and BCR signaling) of erythroblasts, T cells, and B cells, are highly methylated in HSPCs and must be demethylated by TET enzymes to be activated in their respective blood lineages. Many genes required for the maturation, but not for the specification, of monocytes and granulocytes are highly methylated in HSPCs, a condition that does not impede the emergence of these cells but can significantly impair their function. Loss of TET activity leads to severe impairment of hematopoiesis and results in hematological malignancies.

immunology↗

bioRxiv2026

Retinal development driven by TET-dependent DNA demethylation

Inactivation of the TET-dependent DNA demethylation pathway in retinal progenitor cells (RPCs) disrupts retinal development and leads to blindness. In this study, we demonstrated that this is due to the global control exerted by this pathway at all stages of retinal development. TET-deficient RPCs exhibit characteristics of both early and late progenitors, a factor that most likely contributes to the disrupted cellular composition of the retina, wherein the cone population expands significantly at the expense of all other cell types. The differentiation of TET-deficient RPCs also results in the formation of populations of abnormal retinal cell types, a phenomenon particularly evident in the development and function of rod and cone photoreceptors. This global control of a single epigenetic pathway is explained by the high level of methylation in RPCs of many genes critical for retinal development. These genes must be demethylated by TET enzymes to be activated in developing retina.

developmental biology↗

bioRxiv2024

Genetic ablation of the DNA demethylation pathway in retinal progenitor cells impairs photoreceptor development and function, leading to retinal dystrophy

Rod and cone photoreceptors are critical for vision, and their loss leads to blindness. Photoreceptors are epigenetically unique, because the promoters of the genes required for the development and function of these neurons are hypermethylated in retinal progenitor cells (RPCs) and hypomethylated in photoreceptors. However, the mechanism responsible for DNA demethylation during the differentiation of RPCs into photoreceptors and its role in photoreceptor development and function were unknown. We hypothesized that the Ten-Eleven Translocation (TET) family of dioxygenases plays a key role in this mechanism. To this end, we knocked out all TET genes in RPCs and characterized the TET-deficient and control retinas using various approaches including electron microscopy, electroretinogram (ERG) tests, RNA-seq, whole genome bisulfite sequencing (WGBS), and 5hmC-Seal. We found that genetic ablation of the TET family prevents demethylation of the promoters of genes essential for rod specification and for rod and cone maturation during the differentiation of RPCs into photoreceptors. Preservation of methylated cytosines in the promoters of these genes significantly reduced their expression, which was confirmed by western blot analysis. This impaired expression leads to the underdevelopment or complete absence of outer segments and synaptic termini in the photoreceptors of TET-deficient retinas, which results in loss of rod and cone function, as assayed by ERG. These function-deprived, underdeveloped photoreceptors die over time, which leads to blindness.

neuroscience↗