Laboratory Asifa Akhtar

Laboratory Asifa Akhtar

Chromatin Regulation

The Akhtar lab is fascinated by the lysine acetyltransferase MOF (KAT8) responsible for acetylation of histone H4 at the lysine 16 residue (H4K16ac). Although many histone marks exert their influence on transcription by altering the recruitment of chromatin factors, H4K16ac is a rare mark that has been shown to directly modulate chromatin structure by increasing the distance between H4 and H2A surfaces on adjacent nucleosomes, resulting in increased chromatin accessibility. MOF can be found in two multi-subunit chromatin-associated complexes: the MSL complex and the NSL complex. The protein constituents of both complexes are conserved from flies to mammals. In addition, the MSL complex in flies harbours two long non-coding RNAs, roX1 and roX2, which are required for nucleation of complex assembly on the male X chromosome.

Mission

MOF carries out different functions depending on its molecular, physiological and species context. At a given time, MOF can either associate with the MSL or the NSL complex. A central question is therefore how MOF makes the “choice” between interacting with the MSL or the NSL complex and the functional consequences of that “choice”. We are also intrigued by the similarities and differences in NSL and MSL complex function across species. For example, the MSL complex primarily regulates X chromosome-associated genes in flies, but regulates a mix of autosomal and X-chromosomal targets in mammals.

Goals

The Akhtar lab is interested understanding how the two epigenetic mechanisms of histone acetylation and long non-coding RNA are able to finetune gene expression in order to achieve the appropriate levels for a given cell at that particular time. We do this by gaining fundamental insights into the targeting, mechanistic mode of action, and physiological roles of the lysine acetyltransferase MOF and its associated complexes. We have recently discovered that MOF acetylates multiple non-histone substrates (Karoutas et al 2019) as well as functions in regulating transcription from the non-chromatinized mitochondrial genome (Chatterjee et al 2016).

Approach

We are excited by new technologies and so our portfolio of research methodologies continues to expand. At present we adopt an interdisciplinary approach combining biochemistry, genetics, imaging and the latest deep-sequencing methodologies for evaluating transcription, histone modifications, chromatin binding, chromatin accessibility and chromosome conformation. In addition, the lab employs a range of model systems: primarily we have been using the fly as a model system, but have recently expanded into mouse models and human cells to look at evolutionary comparisons.

Impact

Our work has shed light on the molecular mechanisms of dosage compensation in flies as well as histone acetylation-mediated gene regulation in both flies and mammals. The critical functions of MOF-associated complexes in mammals are underscored by the discovery of developmental syndromes resulting from mutations in the genes encoding MSL complex member MSL3 (Basilicata et al 2018 Nature Genetics) and NSL complex member KANSL1 (Koolen de Vries syndrome).


Selected publications

1.
Keller Valsecchi CI , Basilicata MF, Georgiev P, Gaub A, Seyfferth J, Kulkarni T, Panhale A, Semplicio G, Manjunath V, Holz H, Dasmeh P, Akhtar A (2021)
RNA nucleation by MSL2 induces selective X chromosome compartmentalization
Nature 589(7840), 137-142.
2.
Sheikh BN, Guhathakurta S, Tsang TH, Schwabenland M, Renschler G, Herquel B, Bhardwaj V, Holz H, Stehle T, Bondareva O, Aizarani N, Mossad O, Kretz O, Reichardt W, Chatterjee A, Braun LJ, Thevenon J, Sartelet H, Blank T, Grün D, von Elverfeldt D, Huber TB, Vestweber D, Avilov S, Prinz M, Buescher JM and Akhtar A (2020)
Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature
Nature Cell Biology 22(7), 828-841.
3.
Samata M, Alexiadis A, Richard G, Georgiev P, Nübler J, Kulkarni T, Renschler G,  Basilicata MF, Zenk FL, Shvedunova M, Semplicio G, Mirny L, Iovino N and Akhtar A (2020)
Intergenerationally maintained Histone H4 lysine 16 acetylation is instructive for future gene activation
Cell 182(1), 127-144.e23.
4.
Karoutas A, Szymanski W, Rausch T, Guhathakurta S, Rog-Zielinska EA, Peyronnet R, Seyfferth J, Chen HR, de Leeuw R, Herquel B, Kimura H, Mittler G, Kohl P, Medalia O, Korbel JO, Asifa Akhtar (2019)
The NSL complex maintains nuclear architecture stability via Lamin A/C acetylation.
Nature Cell Biology 21, 1248-1260.
5.
Basilicata MF, Bruel AL, Semplicio G, Keller Valsecchi CI, Aktaş T, Duffourd Y, Rumpf T, Morton J, Bache J, Szymanski WG, Gilissen G, Vanakker C, Õunap K, Mittler G, van der Burgt I, El Chehadeh S, Cho MT, Pfundt R, Tan TY, Kirchhoff M, Menten B, Vergult S, Lindstrom K, Reis A, Johnson DS, Fryer A, McKay V, Study DDD, Fisher RB, Thauvin-Robinet C, Francis D, Roscioli T, Pajusalu S, Radtke K, Ganesh J, Brunner HG, Wilson M, Faivre L, Kalscheuer VM, Thevenon J & Akhtar A (2018)
De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation
Nature Genetics 50, 1442–1451.

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