Biology subjects

Lindehell, H.

Publications and source records attributed to Lindehell, H..

3 recordsLinked to original sources

bioRxiv2024

HIF2α negatively regulates MYCN protein levels and promotes a low-risk noradrenergic phenotype in neuroblastoma.

The role of HIF2, encoded by EPAS1, in neuroblastoma remains controversial. Here we demonstrate that induction of high levels of HIF2 in MYCN-amplified neuroblastoma cells results in a rapid and profound reduction of the oncoprotein MYCN. This is followed by an upregulation of genes characteristic of noradrenergic cells in the adrenal medulla. Additionally, upon induction of HIF2, the proliferation rate drops substantially, and cells develop elongated neurite-like protrusions, indicative of differentiation. In vivo HIF2 induction in established xenografts significantly attenuates tumour growth. Notably, analysis of sequenced neuroblastoma patient samples, revealed a negative correlation between EPAS1 and MYCN expression and a strong positive correlation between EPAS1 expression, high expression levels of noradrenergic markers, and improved patient outcome. This was paralleled by analysis of human adrenal medulla datasets wherein EPAS1 expression was prominent in populations with high expression levels of genes characteristic of noradrenergic chromaffin cells. Our findings show that high levels of HIF2 in neuroblastoma, leads to drastically reduced MYCN protein levels, cell cycle exit, and noradrenergic cell differentiation. Taken together, our results challenge the dogma that HIF2 acts as an oncogene in neuroblastoma and rather suggest that HIF2 has potential tumour suppressor capacity in this particular disease. Significance statementHIF2 has been proposed as a neuroblastoma oncogene and a tractable target for clinical intervention, this has been questioned by several studies. Thus, it is necessary to move beyond correlative studies and better determine the function of HIF2 in neuroblastoma. Our study shows that induced expression of HIF2 in MYCN-amplified neuroblastoma substantially reduces MYCN protein levels and attenuates proliferation while it induces several features of noradrenergic differentiation and impedes xenograft tumour growth. Together with bioinformatic analysis of sequenced neuroblastoma patient samples and the developing human adrenal medulla, this couples HIF2 to low-risk neuroblastoma with a substantially better patient outcome. Thus, in neuroblastoma HIF2 exhibit tumour suppressor capacity rather than oncogenic capacity.

cancer biology↗

bioRxiv2021

The role of H3K36 methylation and associated methyltransferases in chromosome-specific gene regulation

In Drosophila, two chromosomes require special mechanisms to balance their transcriptional output to the rest of the genome. These are the male-specific lethal complex targeting the male X-chromosome, and Painting of fourth targeting chromosome 4. The two systems are evolutionarily linked to dosage compensation of the X-chromosome and the chromosomes involved display specific chromatin structures. Here we explore the role of histone H3 tri-methylated at lysine 36 (H3K36me3) and the associated methyltransferases in these two chromosome-specific systems. We show that the loss of Set2 impairs the MSL complex mediated dosage compensation; however, the effect is not recapitulated by H3K36 replacement and indicates an alternative target of Set2. Unexpectedly, balanced transcriptional output from the 4th chromosome requires intact H3K36 and depends on the additive functions of NSD and the Trithorax group protein Ash1. We conclude that H3K36 methylation and the associated methyltransferases are important factors to balance transcriptional output of the male X-chromosome and the 4th chromosome. Furthermore, our study highlights the pleiotropic effects of these enzymes.

genetics↗

bioRxiv2021

DamID transcriptional profiling identifies the Snail/Scratch transcription factor Kahuli as Alk target in the Drosophila visceral mesoderm.

Development of the midgut visceral muscle of Drosophila crucially depends on Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) signalling, which is needed to specify founder cells (FCs) in the circular visceral mesoderm (VM). While activation of the Alk receptor by its ligand Jelly Belly (Jeb) is well characterized, only a small number of target molecules have been identified. Here, we assayed RNA polymerase II (Pol II) occupancy in VM cells by using the targeted DamID (TaDa) approach. To identify Alk targets we employed comparative analysis of embryos overexpressing Jeb versus embryos with abrogated Alk activity, revealing differential expression of a number of genes, including the Snail/Scratch family transcription factor Kahuli (Kah). Upon further in vivo validation, we confirmed that Alk signalling regulates Kah mRNA expression in the VM. We show that Kah mutants display defects in the formation of midgut constrictions, similar to that of pointed (pnt) mutants. Analysis of publicly available ChIP data defined a Kah target-binding site similar to that of Snail. In addition, we compared genes that were differentially expressed in Kah mutants with publicly available Kah- and Pnt-ChIP datasets identifying a set of common target genes putatively regulated by Kah and Pnt in midgut constriction. Taken together, we (i) report a rich dataset of Alk responsive loci in the embryonic VM, (ii) provide the first functional characterization of the Kah transcription factor, identifying a role in embryonic midgut constriction, and (iii) suggest a model in which Kah and Pnt cooperate in embryonic midgut morphogenesis.

developmental biology↗