Biology subjects

Ungerback, J.

Publications and source records attributed to Ungerback, J..

3 recordsLinked to original sources

bioRxiv2025

Chromatin interaction-based annotation of distal cis-regulatory elements reveals highly dynamic promoter-enhancer interactions in lymphocyte development

Stage- and lineage-specific gene expression patterns are controlled by a complex interplay between transcription factors, the epigenetic landscape, and the 3-dimensional (3D) structure of the DNA. The 3D structure allows for the formation of DNA loops that juxtaposition distal regulatory elements to the promoters, allowing for tight control of gene expression. These loops can span hundreds of thousands base pairs, making it challenging to link regulatory elements to the correct target genes using conventional proximity-based annotation methods. Using a novel tool to facilitate the exploration of complex gene regulatory networks based on chromosome configuration data in early lymphocytes, we show that lineage-specific transcription factors target regulatory elements that are annotated to both lineage-specific and broadly expressed genes. Targeted inactivation of a set of these genes revealed their importance for B-cell development. Several regulatory elements annotated to lineage-specific genes were also annotated to alternative promoters in a context dependent manner, revealing a highly complex interplay between promoters and DREs in early lymphocyte development. Investigating the chromatin configuration in EBF1 deficient pro-B cells identified this transcription factor as a key mediator in the establishment of the 3-D promoter enhancer landscape in early B-lymphocyte differentiation. These data highlight how efficient annotation procedures for linking distal regulatory elements to target genes provide valuable insights into gene regulatory networks.

bioinformatics↗

bioRxiv2024

NK cells control the progression of myelodysplastic syndrome but become initial disease target in NUP98-HOXD13 mouse model

Studies in NUP98/HOXD13 mouse model (NHD13tg), progressing from myelodysplastic syndrome (MDS) to different forms of leukemia, demonstrated that T cells had a limited anti-leukemia effect, suggesting the involvement of other immune cells. Natural killer (NK) cells control viral infection and cancer. In MDS and acute myeloid leukemia (AML), patients often acquire disease-induced NK cell dysfunctions. Here, we report that NK cells from NHD13tg mice were reduced before the MDS-onset and specific NK cell depletion accelerated the disease progression and severity. NK cells from NHD13tg mice showed perturbed differentiation and impaired IL-15/IL-2 responses. These defects were cell-intrinsic and mainly affected the KLRG1+ mature NK cells. The expression of Nfil3, Klf2 and Id2 genes, crucial for NK cell development, homeostasis and IL-15 responsiveness, was altered in immature NK cells from NHD13tg mice. Interestingly, these genes were changed in MDS and AML bone marrow patient-samples compared to healthy donors. Our findings highlight a critical role for NK cells in controlling MDS progression and identify new genetic markers for MDS and AML.

immunology↗

bioRxiv2018

Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by PU.1

PU.1 is a dominant but transient regulator in early T-cell precursors and a potent transcriptional controller of developmentally important pro-T cell genes. Before T-lineage commitment, open chromatin is frequently occupied by PU.1, and many PU.1 sites lose accessibility when PU.1 is later downregulated. Pioneering activity of PU.1 was tested in in this developmentally dynamic context, by quantitating the relationships between PU.1 occupancy and site quality and accessibility as PU.1 levels naturally declined in pro-T cell development, and by using stage-specific gain and loss of function perturbations to relate binding to effects on target genes. PU.1 could bind closed genomic sites, but rapidly opened many of them, despite the absence of its frequent collaborators, C/EBP factors. The dynamic properties of PU.1 engagements implied that PU.1 binding affinity and concentration determine its occupancy choices, but with quantitative tradeoffs for occupancy between site sequence quality and stage-dependent site accessibility in chromatin. At non-promoter sites PU.1 binding criteria were more stringent than at promoters, and PU.1 was also much more effective as a transcriptional regulator at non-promoter sites where local chromatin accessibility depended on the presence of PU.1. Runx motifs and Runx1 binding were often linked to PU.1 at open sites, but highly expressed PU.1 could bind its sites without Runx1. Notably, closed chromatin presented a qualitative barrier to occupancy by the PU.1 DNA binding domain alone. Thus, effective pioneering at closed chromatin sites also depends on requirements beyond site recognition served by non-DNA binding domains of PU.1.

immunology↗