lo 4 Dysregulation of the histone code in human disease

What are chromatinopathies?

Neurodevelopmental disorders caused by mutations in genes at each level of chromatin organization

What is Rubenstein-Taybi Syndrome caused by?

Errors in one of two genes: CREBBP or P300

What is the function of CREBBP and P300?

They acetylate histones to promote chromatin accessibility and activate transcription

What type of genetic change causes Rubenstein-Taybi Syndrome?

Haploinsufficiency (dose dependent dominant loss of function) of Histone acetyltransferases

What are the characteristic clinical features of Rubenstein-Taybi Syndrome?

Mental and growth retardation, and dysmorphia of face, feet and hands

What happens when P300 and CBP heterozygous mice are crossed?

Double heterozygous mice (P300+/- , CBP+/-) are perinatal lethal

What does the perinatal lethality of double heterozygous P300/CBP mice reveal?

Haploinsufficiency of these two HATs contributes to the lethal phenotype

What is Kabuki Syndrome caused by?

Mutations in either KMT2D (MLL4) or KDM6A (UTX)

What are KMT2D and KDM6A?

Both are subunits of the COMPASS complex

What type of mutations typically cause Kabuki Syndrome?

Frameshift or nonsense mutations (likely loss of function)

What happens to MLL4 single knockout mice?

They are early embryonic lethal

Could reductions in MLL4 impact cell fate decisions?

Yes, reductions in MLL4 could impact cell fate decisions and timely activation in lineage specific enhancers

What is EZH2 associated with?

Weavers syndrome (a chromatinopathy)

What is ASXL1 associated with?

Bohring-Opitz syndrome (a chromatinopathy)

Are chromatin regulator mutations common in developmental disorders?

Yes, many chromatin modifiers/regulators have been identified as the sole mutated gene in patients with rare developmental disorders

Why do chromatin regulator mutations cause many varied symptoms?

Due to their specific functions in controlling cell fate decisions

Are there drugs that target histone modifications?

Yes, including drugs targeting BRD2/3/4, HDACs, EZH1/2, EED, and DOT1L

Can histone modifications be targeted therapeutically?

Yes, examples include tazemetostat (EZH2 inhibitor) and various bromodomain inhibitors

Is the histone code truly a code?

The answer depends on cellular context, histone residue position, presence of redundant histone modifications, and previous transcriptional state

What makes understanding the histone code complex?

The cellular context (differentiation vs static model system), histone residue position, presence of redundant histone modifications, and previous transcriptional state of a gene

Can some histone modifications maintain an existing state without changing a previous one?

Yes, some histone modifications can maintain an existing state but not change a previous one al