Contact Us

What is JoVE Visualize?

DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor

Affiliations
  • 1Laboratory of Epigenetics and Chromatin Dynamics, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC B11, Lund University, Lund, Sweden.
  • 2Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC A11, Lund University, Lund, Sweden.
  • 3Lund Stem Cell Center, Lund University, Lund, Sweden.
  • 4Division of Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
  • 5Laboratory of Stem Cells and Restorative Neurology, Department of Clinical Sciences, BMC B10, Lund University, Lund, Sweden.
  • 6Laboratory of Epigenetics and Chromatin Dynamics, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC B11, Lund University, Lund, Sweden. christopher.douse@med.lu.se.
  • 7Lund Stem Cell Center, Lund University, Lund, Sweden. christopher.douse@med.lu.se.

|

August 30, 2024

Abstract

The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 and other effectors to remodel chromatin. How HUSH and MORC2 operate alongside DNA methylation, a central epigenetic regulator of repeat transcription, remains largely unknown. Here we interrogate this relationship in human neural progenitor cells (hNPCs), a somatic model of brain development that tolerates removal of DNA methyltransferase DNMT1. Upon loss of MORC2 or HUSH subunit TASOR in hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation and activation of evolutionarily-young L1s attracts MORC2 binding, and simultaneous depletion of DNMT1 and MORC2 causes massive accumulation of L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites and clustered protocadherin genes, repetitive elements important for chromosome structure and neurodevelopment respectively. Our data delineate the epigenetic control of repeats in somatic cells, with implications for understanding the vital functions of HUSH-MORC2 in hypomethylated contexts throughout human development.

Related Concept Videos

JoVE Research Video for Epigenetic Regulation 01:46

30.2K

Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.

In most mammals, females have two X chromosomes (XX) while males have an X and a Y chromosome (XY). The X chromosome contains significantly more genes than the Y chromosome. Therefore, to prevent an excess of X chromosome-linked gene expression in females, one of the two X chromosomes is randomly silenced during early development….

JoVE Research Video for Spreading of Chromatin Modifications 02:25

7.8K

The histone proteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.
Writers
The writer…

JoVE Research Video for Histone Modification 02:32

12.1K

The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone…

JoVE Research Video for Heterochromatin 02:38

8.7K

The extent of chromatin compaction can be studied by staining chromatin using specific DNA binding dyes. Under the microscope, the dense-compacted regions that take up more dye are called heterochromatin. Heterochromatin is further classified into two forms – constitutive heterochromatin and facultative heterochromatin.
Constitutive heterochromatin: It is a highly compact region of chromatin that is mostly concentrated in the centromere and telomere. Unlike euchromatin, the amino acid at…

JoVE Research Video for Restriction Enzymes 01:11

28.4K

Restriction enzymes are bacterial enzymes used to cut DNA in a sequence-specific manner. To cleave DNA, they bind to specific palindromic sequences called restriction sites. Such palindromic DNA sequences or inverted repeats are commonly found in regions of functional significance, such as the origin of replication, gene operator sites, and regions containing transcription termination signals.
The host bacteria protect their own genomic DNA from these enzymes by methylating these sites. Some…

JoVE Research Video for Duplication of Chromatin Structure 02:05

5.0K

The process of chromosome duplication during cell division requires genome-wide disruption and re-assembly of chromatin. The chromatin structure must be accurately inherited, reassembled, and maintained in the daughter cells to ensure lineage propagation.
The basic unit of the chromatin is the nucleosome, consisting of DNA wrapped around octameric histone proteins and short stretches of linker DNA separating individual nucleosomes. The histone proteins within the nucleosome have their…