Simply Put
In all our cells, the DNA is tightly packaged with proteins into a structure called chromatin. This packaging of the DNA into chromatin helps not only to fit the 2 meters of DNA into the small cell nucleus, but also controls which DNA regions (genes) are turned “on” or “off” and thus if the information encoded in a gene is used. Specialized proteins the so-called histones play a key role in this DNA packaging, including the “linker” histone H1 that helps to organize DNA into higher-order structures.
Cells carry important “epigenetic” information – chemical marks on both DNA and the histone proteins – that influences gene activity without changing the DNA sequence itself. When cells divide (and with this also duplicate their DNA), this information must be accurately passed on to daughter cells. While we understand how some histone proteins are correctly inherited after DNA duplication and restored to the correct places in the genome, it remains unclear how the histone H1 proteins are restored and which role H1 plays in preserving such epigenetic memory.
Our research aims to uncover how H1 proteins are reassembled in chromatin after each cell division and how they contribute to maintaining epigenetic information and memory. We will use advanced genomic techniques to track different H1 proteins and compare them to other histones.
We will also study what happens during mitosis (the segregation of duplicated chromosomes into daughter cells), when DNA becomes highly compacted and many proteins are temporarily removed. Some proteins remain on chromatin and may help to preserve epigenetic memory – a process known as “bookmarking.” We aim to understand whether H1 is involved in this bookmarking and transmission of epigenetic information.
In summary, we will address key questions about how chromatin is preserved across cell divisions and how H1 proteins contribute to epigenetic mechanisms.
Description
In eukaryotic cells DNA is, with the help of histone proteins organized in a structure called chromatin. Chromatin allows compaction and storage of the DNA in the nucleus and at the same time access to the DNA when it is needed for e.g. the transcription or replication machineries. Nucleosomes (formed by a core histone H3, H4, H2A and H2B protein octamer and the 147bp of DNA wrapped around it) form the building blocks of chromatin. The linker histone H1 binds to the nucleosome and the linker DNA (between two nucleosomes). H1 binding stabilizes the position of the nucleosome and contributes to higher order chromatin structures. Up to 11 different H1 proteins (so called subtypes or variants) can be expressed, adding an additional level of complexity. “Epigenetic” information can be stored as chemical modifications of DNA and of histone proteins. Such modifications can e.g. regulate DNA accessibility or recruit so called “reader” proteins that then regulate downstream processes, such as transcription or replication. Cell divisions and DNA replication are major disruptions of chromatin and thus for the transmission of epigenetic information into daughter cells.
After DNA replication, nucleosomes are rapidly reassembled onto the newly synthesized DNA. Parental histones H3–H4 are accurately recycled, as tetramers, with their modifications to the two daughter DNA strands whereas “new” core histones (H3/H4 tetramers and H2A/H2B dimers) fill the gaps between the old ones. The equal inheritance of “old” histones (recycling) to both DNA strands is considered crucial for maintaining epigenome fidelity and memory as only the old ones transmit histone marks, guiding correct re-establishment of heterochromatin and euchromatin domains and thus information for future gene expression. In contrast to core histones, we do not know how and when the linker H1 is restored after DNA replication and whether there are differences in inheritance patterns and timing between the H1 subtypes and between different genomic regions.
To understand epigenetic memory at the molecular level, a breakthrough would be to determine when histone H1 is reassembled on chromatin after each cell division and what are the mechanisms underlying this. We will apply a combination of “omics” techniques (both proteomics and next generation sequencing based) to study the restoration of individual H1 subtypes and variants and compare this systematically with core histones and their modifications. With the support from Aging Biology Foundation, we plan to uncover the mechanisms of H1 inheritance through replication and chromatin reassembly.
A second major challenge to chromatin is mitosis. In mitosis (M-phase) chromosomes become highly condensed and the protein composition of chromatin changes majorly. While many chromatin components are displaced, others stay (so called mitotic bookmarking) and thus could carry epigenetic information. With the support of the Aging Biology Foundation, we want to unravel the role of histone H1 in transmitting epigenetic information through mitosis.
In summary, we will address key questions about how chromatin states are preserved across cell divisions and how H1 and its multiple subtypes contribute to epigenetic mechanisms.