Research

The Lindroth lab is pursuing research on epigenetic regulation in cancer with special focus on DNA methylation. Of particular interest is how DNA methylation is targeted to specific areas of the genome. The interactions with other epigenetic modifications are also highly relevant as they commonly cooperate and provide a dynamic framework for gene expression regulation and chromosomal integrity.

 1.     Identification of a maintenance DNA methyltransferase CMT3 contributing to maintaining silencing at a developmental locus in plants (Lindroth AM, et al., Science, 2001). The gene silencing was further enforced in conjunction with H3K9 methylation by the histone methyltransferase SUVH4 (Jackson JP, et al., Nature, 2002).

2.     DNA methylation and H3K27 methylation display a mutual antagonism at the Rasgrf1 locus, essential in the imprinting pattern that govern maternal and paternal expression of Rasgrf1 in mice (Lindroth AM, et al., PLoS Genetics, 2008).

3.     Pediatric glioblastoma (pedGBM) is driven by histone variant H3.3 mutations (Schwartzentruber J, et al., Nature, 2012).

4.     Epigenetic characterization of histone variant H3.3 mutations in pediatric glioblastoma find that H3.3-K27M blocks global acquisition of H3K27 methylation and change DNA methylation pattern, and H3.3-G34R/V produce hypomethylation at telomeric areas (Sturm D, et al., Cancer Cell, 2012).

5.     Giant cell tumor of bone (GCTB) is frequently mutated (>90%) to generate H3.3-G34W, which occur in long bones predominantly at the distal femur. H3.3-G34W leads to altered RNA processing leading to splicing aberrations (Lim J, et al., Scientific Reports, 2017).

6.     Comprehensive epigenomic characterization of GCTB indicate that H3.3-G34W have limited global effect on epigenetic modification, with the exception of loss H3K36 methylation in cis and reduced DNA methylation by about 20% at large methylated domains (Lutsik P, Nature Communications, 2020).