Autonomous transposons tune their sequences to ensure somatic suppression.

Transposable elements (TEs) are a major constituent of human genes, occupying approximately half of the intronic space. During pre-messenger RNA synthesis, intronic TEs are transcribed along with their host genes but rarely contribute to the final mRNA product because they are spliced out together with the intron and rapidly degraded. Paradoxically, TEs are an abundant source of RNA-processing signals through which they can create new introns1, and also functional2 or non-functional chimeric transcripts3. The rarity of these events implies the existence of a resilient splicing code that is able to suppress TE exonization without compromising host pre-mRNA processing. Here we show that SAFB proteins protect genome integrity by preventing retrotransposition of L1 elements while maintaining splicing integrity, via prevention of the exonization of previously integrated TEs. This unique dual role is possible because of L1's conserved adenosine-rich coding sequences that are bound by SAFB proteins. The suppressive activity of SAFB extends to tissue-specific, giant protein-coding cassette exons, nested genes and Tigger DNA transposons. Moreover, SAFB also suppresses LTR/ERV elements in species in which they are still active, such as mice and flies. A significant subset of splicing events suppressed by SAFB in somatic cells are activated in the testis, coinciding with low SAFB expression in postmeiotic spermatids. Reminiscent of the division of labour between innate and adaptive immune systems that fight external pathogens, our results uncover SAFB proteins as an RNA-based, pattern-guided, non-adaptive defence system against TEs in the soma, complementing the RNA-based, adaptive Piwi-interacting RNA pathway of the germline.

Cerebral perfusion in type 2 diabetes mellitus: A preliminary study with MR perfusion.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with altered cerebral vasoreactivity, cognitive impairment, and functional decline. Magnetic Resonance (MR) perfusion can be used to assess cerebral blood flow (CBF). The aim of this study is to analyze the association between diabetes mellitus and cerebral perfusion. METHODS: The study included 52 patients diagnosed with T2DM and 39 healthy individuals. The diabetic patients were classified into three groups (PRP: proliferative retinopathy, NPRP: non-proliferative retinopathy, Non-RP: non-retinopathy DM). The rCBF measurements of cortical gray matter and thalami were carried out using the region of interest. Reference quantitative measurements were performed from ipsilateral white matter. RESULTS: The comparison between the T2DM group and the control group revealed that rCBF values of bilateral frontal lobes, cingulate gyrus, medial temporal lobe, thalami and right occipital lobe were measured to be significantly lower in the T2DM group (p < 0.05). No significant difference was detected between the two groups in terms of rCBF values of the left occipital lobe and anterior aspect of the left temporal lobe (p > 0.05). The rCBF values were lower in the anterior aspect of the right temporal lobe and the difference showed borderline statistical significance (p = 0.058). No significant difference was detected regarding mean rCBF values measured in the regions of cerebral hemispheres among the three patient groups with T2DM (p˃0.05). CONCLUSION: Regional hypoperfusion was encountered in most of the lobes in the T2DM group when compared with the healthy group. However, in terms of rCBF values, there was no significant difference among the three groups with T2DM.

Dynamic antagonism between key repressive pathways maintains the placental epigenome.

DNA and Histone 3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb repressive complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extra-embryonic lineages display non-canonical, globally intermediate DNA methylation levels, including disruption of local Polycomb domains. Here, to better understand this unusual landscape's molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse trophoblast stem cells. We find that the extra-embryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extra-embryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation.

A multi-factor trafficking site on the spliceosome remodeling enzyme BRR2 recruits C9ORF78 to regulate alternative splicing.

The intrinsically unstructured C9ORF78 protein was detected in spliceosomes but its role in splicing is presently unclear. We find that C9ORF78 tightly interacts with the spliceosome remodeling factor, BRR2, in vitro. Affinity purification/mass spectrometry and RNA UV-crosslinking analyses identify additional C9ORF78 interactors in spliceosomes. Cryogenic electron microscopy structures reveal how C9ORF78 and the spliceosomal B complex protein, FBP21, wrap around the C-terminal helicase cassette of BRR2 in a mutually exclusive manner. Knock-down of C9ORF78 leads to alternative NAGNAG 3'-splice site usage and exon skipping, the latter dependent on BRR2. Inspection of spliceosome structures shows that C9ORF78 could contact several detected spliceosome interactors when bound to BRR2, including the suggested 3'-splice site regulating helicase, PRPF22. Together, our data establish C9ORF78 as a late-stage splicing regulatory protein that takes advantage of a multi-factor trafficking site on BRR2, providing one explanation for suggested roles of BRR2 during splicing catalysis and alternative splicing.

The intrinsically disordered TSSC4 protein acts as a helicase inhibitor, placeholder and multi-interaction coordinator during snRNP assembly and recycling.

Biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs) and their recycling after splicing require numerous assembly/recycling factors whose modes of action are often poorly understood. The intrinsically disordered TSSC4 protein has been identified as a nuclear-localized U5 snRNP and U4/U6-U5 tri-snRNP assembly/recycling factor, but how TSSC4's intrinsic disorder supports TSSC4 functions remains unknown. Using diverse interaction assays and cryogenic electron microscopy-based structural analysis, we show that TSSC4 employs four conserved, non-contiguous regions to bind the PRPF8 Jab1/MPN domain and the SNRNP200 helicase at functionally important sites. It thereby inhibits SNRNP200 helicase activity, spatially aligns the proteins, coordinates formation of a U5 sub-module and transiently blocks premature interaction of SNRNP200 with at least three other spliceosomal factors. Guided by the structure, we designed a TSSC4 variant that lacks stable binding to the PRPF8 Jab1/MPN domain or SNRNP200 in vitro. Comparative immunoprecipitation/mass spectrometry from HEK293 nuclear extract revealed distinct interaction profiles of wild type TSSC4 and the variant deficient in PRPF8/SNRNP200 binding with snRNP proteins, other spliceosomal proteins as well as snRNP assembly/recycling factors and chaperones. Our findings elucidate molecular strategies employed by an intrinsically disordered protein to promote snRNP assembly, and suggest multiple TSSC4-dependent stages during snRNP assembly/recycling.

Nuclear speckles: dynamic hubs of gene expression regulation.

Complex, multistep biochemical reactions that routinely take place in our cells require high concentrations of enzymes, substrates, and other structural components to proceed efficiently and typically require chemical environments that can inhibit other reactions in their immediate vicinity. Eukaryotic cells solve these problems by restricting such reactions into diffusion-restricted compartments within the cell called organelles that can be separated from their environment by a lipid membrane, or into membrane-less compartments that form through liquid-liquid phase separation (LLPS). One of the most easily noticeable and the earliest discovered organelle is the nucleus, which harbors the genetic material in cells where transcription by RNA polymerases produces most of the messenger RNAs and a plethora of noncoding RNAs, which in turn are required for translation of mRNAs in the cytoplasm. The interior of the nucleus is not a uniform soup of biomolecules and rather consists of a variety of membrane-less bodies, such as the nucleolus, nuclear speckles (NS), paraspeckles, Cajal bodies, histone locus bodies, and more. In this review, we will focus on NS with an emphasis on recent developments including our own findings about the formation of NS by two large IDR-rich proteins SON and SRRM2.

Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration.

Haematopoietic stem cells (HSCs) are normally quiescent, but have evolved mechanisms to respond to stress. Here, we evaluate haematopoietic regeneration induced by chemotherapy. We detect robust chromatin reorganization followed by increased transcription of transposable elements (TEs) during early recovery. TE transcripts bind to and activate the innate immune receptor melanoma differentiation-associated protein 5 (MDA5) that generates an inflammatory response that is necessary for HSCs to exit quiescence. HSCs that lack MDA5 exhibit an impaired inflammatory response after chemotherapy and retain their quiescence, with consequent better long-term repopulation capacity. We show that the overexpression of ERV and LINE superfamily TE copies in wild-type HSCs, but not in Mda5-/- HSCs, results in their cycling. By contrast, after knockdown of LINE1 family copies, HSCs retain their quiescence. Our results show that TE transcripts act as ligands that activate MDA5 during haematopoietic regeneration, thereby enabling HSCs to mount an inflammatory response necessary for their exit from quiescence.

SON and SRRM2 are essential for nuclear speckle formation.

Nuclear speckles (NS) are among the most prominent biomolecular condensates. Despite their prevalence, research on the function of NS is virtually restricted to colocalization analyses, since an organizing core, without which NS cannot form, remains unidentified. The monoclonal antibody SC35, raised against a spliceosomal extract, is frequently used to mark NS. Unexpectedly, we found that this antibody was mischaracterized and the main target of SC35 mAb is SRRM2, a spliceosome-associated protein that sharply localizes to NS. Here we show that, the core of NS is likely formed by SON and SRRM2, since depletion of SON leads only to a partial disassembly of NS, while co-depletion of SON and SRRM2 or depletion of SON in a cell-line where intrinsically disordered regions (IDRs) of SRRM2 are genetically deleted, leads to a near-complete dissolution of NS. This work, therefore, paves the way to study the role of NS under diverse physiological and stress conditions.

Most cells store their genetic material inside a compartment called the nucleus, which helps to separate DNA from other molecules in the cell. Inside the nucleus, DNA is tightly packed together with proteins that can read the cell's genetic code and convert into the RNA molecules needed to build proteins. However, the contents of the nucleus are not randomly arranged, and these proteins are often clustered into specialized areas where they perform their designated roles. One of the first nuclear territories to be identified were granular looking structures named Nuclear Speckles (or NS for short), which are thought to help process RNA before it leaves the nucleus. Structures like NS often contain a number of different factors held together by a core group of proteins known as a scaffold. Although NS were discovered over a century ago, little is known about their scaffold proteins, making it difficult to understand the precise role of these speckles. Typically, researchers visualize NS using a substance called SC35 which targets specific sites in these structures. However, it was unclear which parts of the NS this marker binds to. To answer this question, Ilik et al. studied NS in human cells grown in the lab. The analysis revealed that SC35 attaches to certain parts of a large, flexible protein called SRRM2. Ilik et al. discovered that although the structure and sequence of SRMM2 varies between different animal species, a small region of this protein remained unchanged throughout evolution. Studying the evolutionary history of SRRM2 led to the identification of another protein with similar properties called SON. Ilik et al. found that depleting SON and SRRM2 from human cells caused other proteins associated with the NS to diffuse away from their territories and become dispersed within the nucleus. This suggests that SRMM2 and SON make up the scaffold that holds the proteins in NS together. Nuclear speckles have been associated with certain viral infections, and seem to help prevent the onset of diseases such as Huntington's and spinocerebellar ataxia. These newly discovered core proteins could therefore further our understanding of the role NS play in disease.

Nephronophthisis gene products display RNA-binding properties and are recruited to stress granules.

Mutations of cilia-associated molecules cause multiple developmental defects that are collectively termed ciliopathies. However, several ciliary proteins, involved in gating access to the cilium, also assume localizations at other cellular sites including the nucleus, where they participate in DNA damage responses to maintain tissue integrity. Molecular insight into how these molecules execute such diverse functions remains limited. A mass spectrometry screen for ANKS6-interacting proteins suggested an involvement of ANKS6 in RNA processing and/or binding. Comparing the RNA-binding properties of the known RNA-binding protein BICC1 with the three ankyrin-repeat proteins ANKS3, ANKS6 (NPHP16) and INVERSIN (NPHP2) confirmed that certain nephronophthisis (NPH) family members can interact with RNA molecules. We also observed that BICC1 and INVERSIN associate with stress granules in response to translational inhibition. Furthermore, BICC1 recruits ANKS3 and ANKS6 into TIA-1-positive stress granules after exposure to hippuristanol. Our findings uncover a novel function of NPH family members, and provide further evidence that NPH family members together with BICC1 are involved in stress responses to maintain tissue and organ integrity.

FLASH: ultra-fast protocol to identify RNA-protein interactions in cells.

Determination of the in vivo binding sites of RNA-binding proteins (RBPs) is paramount to understanding their function and how they affect different aspects of gene regulation. With hundreds of RNA-binding proteins identified in human cells, a flexible, high-resolution, high-throughput, highly multiplexible and radioactivity-free method to determine their binding sites has not been described to date. Here we report FLASH (Fast Ligation of RNA after some sort of Affinity Purification for High-throughput Sequencing), which uses a special adapter design and an optimized protocol to determine protein-RNA interactions in living cells. The entire FLASH protocol, starting from cells on plates to a sequencing library, takes 1.5 days. We demonstrate the flexibility, speed and versatility of FLASH by using it to determine RNA targets of both tagged and endogenously expressed proteins under diverse conditions in vivo.

Shear-wave elastography - virtual touch tissue quantification of fetal placentas with a single umbilical artery.

OBJECTIVE: In this study, we aimed to evaluate the elasticities of fetal placentas with a single umbilical artery using the Virtual Touch Tissue Quantification (VTTQ) technique. MATERIALS AND METHODS: Pregnant women with fetuses with a single umbilical artery (SUA) and pregnant women with fetuses having three vessel cord (3VC) at 18-22 weeks of gestation were enrolled in the research. The placentas were evaluated and divided into three equal parts as the inner 1/3 of the placenta (fetal edge), the outer 1/3 of the placenta (maternal edge) and the central 1/3 of the placenta (central part). Shear-wave velocity (SWV) measurements were used in the elastographic evaluation of placentas by VTTQ. RESULTS: Forty pregnant women were included in the study (n = 20 SUA, n = 20 three vessel cord pregnant women). The placental Acoustic Radiation Force Impulse (VTTQ) of the placenta regarding SWV measurement values of the fetal edge of the placenta in the fetuses with SUA and the control group were 0.876 and 0.957 m/sec, respectively. A significant statistical difference was found between the groups regarding the measurement of the stiffness of fetal placenta (p = 0.021). There was no significant difference between the measured stiffness values of the central or outer region of the placentas. CONCLUSIONS: In this study, we found lower SWV scores for the fetal edge of the placenta with SUA. This finding may reflect tissue elasticity level, and we hope that the use of the VTTQ technique may contribute to predicting the pregnancy-related morbidities of fetuses with SUA in the future.

uvCLAP is a fast and non-radioactive method to identify in vivo targets of RNA-binding proteins.

RNA-binding proteins (RBPs) play important and essential roles in eukaryotic gene expression regulating splicing, localization, translation, and stability of mRNAs. We describe ultraviolet crosslinking and affinity purification (uvCLAP), an easy-to-use, robust, reproducible, and high-throughput method to determine in vivo targets of RBPs. uvCLAP is fast and does not rely on radioactive labeling of RNA. We investigate binding of 15 RBPs from fly, mouse, and human cells to test the method's performance and applicability. Multiplexing of signal and control libraries enables straightforward comparison of samples. Experiments for most proteins achieve high enrichment of signal over background. A point mutation and a natural splice isoform that change the RBP subcellular localization dramatically alter target selection without changing the targeted RNA motif, showing that compartmentalization of RBPs can be used as an elegant means to generate RNA target specificity.

Use of ARFI elastography in the prediction of placental invasion anomaly via a new Virtual Touch Quantification Technique.

We aimed to evaluate the efficiency of placental elasticity in predicting a placental invasion anomaly with the Virtual Touch Quantification (VTQ) technique. Pregnant women in the third trimester with suspected placental invasion anomaly were enrolled into the research (n = 58). The placenta was evaluated and divided into three equal parts as foetal edge (inner 1/3 of placenta), maternal edge (outer 1/3 of placenta) and the central part (central 1/3 of placenta). Shear wave velocity (SWV) measurements were used in the elastographic evaluation of placentas by VTQ. We performed the measurements at the different regions of placenta for sampling the variety areas of the placenta. Acoustic Radiation Force Impulse (ARFI) Elastography scores were significantly higher in the group in which an invasion was detected during the surgery of patients with preoperative placental invasion suspicion. A significant difference in the measurements of the inner, central and outer third of the placenta between the groups was found (p < .001). In this study, we have shown higher SWV scores of placental measurements of the patients with preoperative suspected anomalies and an invasion detected during their surgery. These findings may reflect an event at the tissue elasticity level and we hope that the use of the VTQ technique may contribute to an early prediction of placental invasions before surgery in the future via new research. Impact statement What is already known on this subject? Placenta invasion anomalies (PIA's) are characterized by haemorrhages which can threat the mother's life. Placental invasion anomalies are among the most important causes of maternal mortality and morbidity. Early diagnosis is very important condition in reducing the mortality and morbidity. Gray scale ultrasonography (US) is mostly used in early diagnosis of PIA's. Acoustic radiation force impulse elastography (ARFI) is a new elastographic ultrasonography technic. We aimed to evaluate a new method in the early diagnosis of PIA's using ARFI technique. There is no study in the diagnosis of PIA's by ARFI in the literature to our knowledge. We think that this original study will contribute to the literature. What do the results of this study add? We showed the accuracy of ARFI in determination of PIA's. ARFI scores were significantly higher in the group in which invasion was detected during surgery of patients with preoperative placental invasion suspicion. What are the implications are of these findings for clinical practice and/or further research? Our findings may reflect an event at the tissue elasticity level and we hope that the use of VTQ technique may contribute to early predict of placental invasions before surgery in the future via new researches. Early diagnosis of placental invasion anomalies may reduce mortality and morbidity.

A mutually exclusive stem-loop arrangement in roX2 RNA is essential for X-chromosome regulation in Drosophila.

The X chromosome provides an ideal model system to study the contribution of RNA-protein interactions in epigenetic regulation. In male flies, roX long noncoding RNAs (lncRNAs) harbor several redundant domains to interact with the ubiquitin ligase male-specific lethal 2 (MSL2) and the RNA helicase Maleless (MLE) for X-chromosomal regulation. However, how these interactions provide the mechanics of spreading remains unknown. By using the uvCLAP (UV cross-linking and affinity purification) methodology, which provides unprecedented information about RNA secondary structures in vivo, we identified the minimal functional unit of roX2 RNA. By using wild-type and various MLE mutant derivatives, including a catalytically inactive MLE derivative, MLEGET, we show that the minimal roX RNA contains two mutually exclusive stem-loops that exist in a peculiar structural arrangement: When one stem-loop is unwound by MLE, an alternate structure can form, likely trapping MLE in this perpetually structured region. We show that this functional unit is necessary for dosage compensation, as mutations that disrupt this formation lead to male lethality. Thus, we propose that roX2 lncRNA contains an MLE-dependent affinity switch to enable reversible interactions of the MSL complex to allow dosage compensation of the X chromosome.

DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome.

Transposable elements are viewed as 'selfish genetic elements', yet they contribute to gene regulation and genome evolution in diverse ways. More than half of the human genome consists of transposable elements. Alu elements belong to the short interspersed nuclear element (SINE) family of repetitive elements, and with over 1 million insertions they make up more than 10% of the human genome. Despite their abundance and the potential evolutionary advantages they confer, Alu elements can be mutagenic to the host as they can act as splice acceptors, inhibit translation of mRNAs and cause genomic instability. Alu elements are the main targets of the RNA-editing enzyme ADAR and the formation of Alu exons is suppressed by the nuclear ribonucleoprotein HNRNPC, but the broad effect of massive secondary structures formed by inverted-repeat Alu elements on RNA processing in the nucleus remains unknown. Here we show that DHX9, an abundant nuclear RNA helicase, binds specifically to inverted-repeat Alu elements that are transcribed as parts of genes. Loss of DHX9 leads to an increase in the number of circular-RNA-producing genes and amount of circular RNAs, translational repression of reporters containing inverted-repeat Alu elements, and transcriptional rewiring (the creation of mostly nonsensical novel connections between exons) of susceptible loci. Biochemical purifications of DHX9 identify the interferon-inducible isoform of ADAR (p150), but not the constitutively expressed ADAR isoform (p110), as an RNA-independent interaction partner. Co-depletion of ADAR and DHX9 augments the double-stranded RNA accumulation defects, leading to increased circular RNA production, revealing a functional link between these two enzymes. Our work uncovers an evolutionarily conserved function of DHX9. We propose that it acts as a nuclear RNA resolvase that neutralizes the immediate threat posed by transposon insertions and allows these elements to evolve as tools for the post-transcriptional regulation of gene expression.

Rapid evolutionary turnover underlies conserved lncRNA-genome interactions.

Many long noncoding RNAs (lncRNAs) can regulate chromatin states, but the evolutionary origin and dynamics driving lncRNA-genome interactions are unclear. We adapted an integrative strategy that identifies lncRNA orthologs in different species despite limited sequence similarity, which is applicable to mammalian and insect lncRNAs. Analysis of the roX lncRNAs, which are essential for dosage compensation of the single X chromosome in Drosophila males, revealed 47 new roX orthologs in diverse Drosophilid species across ∼40 million years of evolution. Genetic rescue by roX orthologs and engineered synthetic lncRNAs showed that altering the number of focal, repetitive RNA structures determines roX ortholog function. Genomic occupancy maps of roX RNAs in four species revealed conserved targeting of X chromosome neighborhoods but rapid turnover of individual binding sites. Many new roX-binding sites evolved from DNA encoding a pre-existing RNA splicing signal, effectively linking dosage compensation to transcribed genes. Thus, dynamic change in lncRNAs and their genomic targets underlies conserved and essential lncRNA-genome interactions.

Revealing long noncoding RNA architecture and functions using domain-specific chromatin isolation by RNA purification.

Little is known about the functional domain architecture of long noncoding RNAs (lncRNAs) because of a relative paucity of suitable methods to analyze RNA function at a domain level. Here we describe domain-specific chromatin isolation by RNA purification (dChIRP), a scalable technique to dissect pairwise RNA-RNA, RNA-protein and RNA-chromatin interactions at the level of individual RNA domains in living cells. dChIRP of roX1, a lncRNA essential for Drosophila melanogaster X-chromosome dosage compensation, reveals a 'three-fingered hand' ribonucleoprotein topology. Each RNA finger binds chromatin and the male-specific lethal (MSL) protein complex and can individually rescue male lethality in roX-null flies, thus defining a minimal RNA domain for chromosome-wide dosage compensation. dChIRP improves the RNA genomic localization signal by >20-fold relative to previous techniques, and these binding sites are correlated with chromosome conformation data, indicating that most roX-bound loci cluster in a nuclear territory. These results suggest dChIRP can reveal lncRNA architecture and function with high precision and sensitivity.

Tandem stem-loops in roX RNAs act together to mediate X chromosome dosage compensation in Drosophila.

Dosage compensation in Drosophila is an epigenetic phenomenon utilizing proteins and long noncoding RNAs (lncRNAs) for transcriptional upregulation of the male X chromosome. Here, by using UV crosslinking followed by deep sequencing, we show that two enzymes in the Male-Specific Lethal complex, MLE RNA helicase and MSL2 ubiquitin ligase, bind evolutionarily conserved domains containing tandem stem-loops in roX1 and roX2 RNAs in vivo. These domains constitute the minimal RNA unit present in multiple copies in diverse arrangements for nucleation of the MSL complex. MLE binds to these domains with distinct ATP-independent and ATP-dependent behavior. Importantly, we show that different roX RNA domains have overlapping function, since only combinatorial mutations in the tandem stem-loops result in severe loss of dosage compensation and consequently male-specific lethality. We propose that repetitive structural motifs in lncRNAs could provide plasticity during multiprotein complex assemblies to ensure efficient targeting in cis or in trans along chromosomes.

The MOF chromobarrel domain controls genome-wide H4K16 acetylation and spreading of the MSL complex.

The histone H4 lysine 16 (H4K16)-specific acetyltransferase MOF is part of two distinct complexes involved in X chromosome dosage compensation and autosomal transcription regulation. Here we show that the MOF chromobarrel domain is essential for H4K16 acetylation throughout the Drosophila genome and is required for spreading of the male-specific lethal (MSL) complex on the X chromosome. The MOF chromobarrel domain directly interacts with nucleic acids and potentiates MOF's enzymatic activity after chromatin binding, making it a unique example of a chromo-like domain directly controlling acetylation activity in vivo. We also show that the Drosophila-specific N terminus of MOF has evolved to perform sex-specific functions. It modulates nucleosome binding and HAT activity and controls MSL complex assembly, thus regulating MOF function in dosage compensation. We propose that MOF has been especially tailored to achieve tight regulation of its enzymatic activity and enable its dual role on X and autosomes.