4 research outputs found
Bispyrimidines as Potent Histamine H<sub>4</sub> Receptor Ligands: Delineation of Structure–Activity Relationships and Detailed H<sub>4</sub> Receptor Binding Mode
The
basic methylpiperazine moiety is considered a necessary substructure
for high histamine H<sub>4</sub> receptor (H<sub>4</sub>R) affinity.
This moiety is however also the metabolic hot spot for various classes
of H<sub>4</sub>R ligands (e.g., indolcarboxamides and pyrimidines).
We set out to investigate whether mildly basic 2-aminopyrimidines
in combination with the appropriate linker can serve as a replacement
for the methylpiperazine moiety. In the series of 2-aminopyrimidines,
the introduction of an additional 2-aminopyrimidine moiety in combination
with the appropriate linker lead to bispyrimidines displaying p<i>K</i><sub>i</sub> values for binding the human H<sub>4</sub>R up to 8.2. Furthermore, the methylpiperazine replacement results
in compounds with improved metabolic properties. The attempt to transfer
the knowledge generated in the class of bispyrimidines to the indolecarboxamides
failed. Combining the derived structure–activity relationships
with homology modeling leads to new detailed insights in the molecular
aspects of ligand–H<sub>4</sub>R binding in general and the
binding mode of the described bispyrimidines in specific
Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing
Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-Activated, SHH-pathway-Activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context
Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing
Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease contex