3. How is chromatin structure dysregulated in disease

What are structural variants (SVs)?

Structural and quantitative chromosomal rearrangements

How can SVs affect gene expression?

By altering copy number of regulatory elements or disrupting higher-order chromatin organisation

What is a fused TAD?

A TAD caused by deletion of a TAD boundary

What is a neo-TAD?

A new TAD formed by duplication of a genomic region including a TAD boundary

Neo-TADs can be caused by duplication of a genomic region including a TAD boundary (CTCF binding site),

creating

a new chromatin domain.

What is a shuffled TAD?

A TAD caused by inversion of a genomic region

What is enhancer adoption?

Relocation of enhancer elements into a neighbouring TAD causing misexpression

What syndrome is associated with duplications of enhancer elements at the IHH locus?

Synpolydactyly

What is Cooks syndrome and what causes it?

Short digits and nail aplasia caused by duplication of a TAD boundary at the SOX9 locus

What did the Ibrahim lab show by removing CTCF binding motifs between Kcnj2-TAD and Sox9-TAD?

Formation of a larger fused TAD and altered gene expression patterns

What disease is associated with deletion of a TAD boundary at the LMNB1 locus?

Adult-onset demyelinating leukodystrophy

What is F syndrome and what causes it?

Syndactyly of thumb and index finger caused by inversions at the EPHA4 locus

What are chromatinopathies?

Disorders caused by mutations in chromatin regulators

What is Cornelia de Lange Syndrome (CdLS)?

A multisystem developmental disorder caused by mutations in cohesin complex subunits

CdLS is characterised by

facial dysmorphisms, upper limb abnormalities, growth delay, and cognitive retardation.

Which genes are mutated in Cornelia de Lange Syndrome?

NIPBL (~65%),

SMC1A,

SMC3,

RAD21

What is the function of NIPBL?

Loading the cohesin ring onto chromatin

What happens in RAD21 mutations causing CdLS?

Missense mutations cluster at the interface with STAG2 and SMC1A, impairing DNA damage response

How does SMC1A cause CdLS?

Through X-linked recessive inheritance

What happens to TAD structure when CTCF binding sites are deleted at the SOX9-Kcnj2 locus?

Formation of a larger fused TAD

How do structural variants create specific signatures in Hi-C maps?

They produce ectopic interactions visible in interaction maps