Function Of H1 Research Articles

Linker histone H1 drives heterochromatin condensation via phase separation in Arabidopsis.

In the eukaryotic nucleus, heterochromatin forms highly condensed, visible foci known as heterochromatin foci (HF). These HF are enriched with linker histone H1, a key player in heterochromatin condensation and silencing. However, it is unknown how H1 aggregates HF and condenses heterochromatin. In this study, we established that H1 facilitates heterochromatin condensation by enhancing inter- and intrachromosomal interactions between and within heterochromatic regions of the Arabidopsis (Arabidopsis thaliana) genome. We demonstrated that H1 drives HF formation via phase separation, which requires its C-terminal intrinsically disordered region (C-IDR). A truncated H1 lacking the C-IDR fails to form foci or recover HF in the h1 mutant background, whereas C-IDR with a short stretch of the globular domain (18 out of 71 amino acids) is sufficient to rescue both defects. In addition, C-IDR is essential for H1's roles in regulating nucleosome repeat length and DNA methylation in Arabidopsis, indicating that phase separation capability is required for chromatin functions of H1. Our data suggest that bacterial H1-like proteins, which have been shown to condense DNA, are intrinsically disordered and capable of mediating phase separation. Therefore, we propose that phase separation mediated by H1 or H1-like proteins may represent an ancient mechanism for condensing chromatin and DNA.

Density of subalgebras of Lipschitz functions in metric Sobolev spaces and applications to Wasserstein Sobolev spaces

We prove a general criterion for the density in energy of suitable subalgebras of Lipschitz functions in the metric Sobolev space H1,p(X,d,m) associated with a positive and finite Borel measure m in a separable and complete metric space (X,d).We then provide a relevant application to the case of the algebra of cylinder functions in the Wasserstein Sobolev space H1,2(P2(M),W2,m) arising from a positive and finite Borel measure m on the Kantorovich-Rubinstein-Wasserstein space (P2(M),W2) of probability measures in a finite dimensional Euclidean space, a complete Riemannian manifold, or a separable Hilbert space M. We will show that such a Sobolev space is always Hilbertian, independently of the choice of the reference measure m so that the resulting Cheeger energy is a Dirichlet form.We will eventually provide an explicit characterization for the corresponding notion of m-Wasserstein gradient, showing useful calculus rules and its consistency with the tangent bundle and the Γ-calculus inherited from the Dirichlet form.

Single-molecule study reveals Hmo1, not Hho1, promotes chromatin assembly in budding yeast.

Linker histone H1 plays a crucial role in various biological processes, including nucleosome stabilization, high-order chromatin structure organization, gene expression, and epigenetic regulation in eukaryotic cells. Unlike higher eukaryotes, little about the linker histone in Saccharomyces cerevisiae is known. Hho1 and Hmo1 are two long-standing controversial histone H1 candidates in budding yeast. In this study, we directly observed at the single-molecule level that Hmo1, but not Hho1, is involved in chromatin assembly in the yeast nucleoplasmic extracts (YNPE), which can replicate the physiological condition of the yeast nucleus. The presence of Hmo1 facilitates the assembly of nucleosomes on DNA in YNPE, as revealed by single-molecule force spectroscopy. Further single-molecule analysis showed that the lysine-rich C-terminal domain (CTD) of Hmo1 is essential for the function of chromatin compaction, while the second globular domain at the C-terminus of Hho1 impairs its ability. In addition, Hmo1, but not Hho1, forms condensates with double-stranded DNA via reversible phase separation. The phosphorylation fluctuation of Hmo1 coincides with metazoan H1 during the cell cycle. Our data suggest that Hmo1, but not Hho1, possesses some functionality similar to that of linker histone in Saccharomyces cerevisiae, even though some properties of Hmo1 differ from those of a canonical linker histone H1. Our study provides clues for the linker histone H1 in budding yeast and provides insights into the evolution and diversity of histone H1 across eukaryotes. IMPORTANCE There has been a long-standing debate regarding the identity of linker histone H1 in budding yeast. To address this issue, we utilized YNPE, which accurately replicate the physiological conditions in yeast nuclei, in combination with total internal reflection fluorescence microscopy and magnetic tweezers. Our findings demonstrated that Hmo1, rather than Hho1, is responsible for chromatin assembly in budding yeast. Additionally, we found that Hmo1 shares certain characteristics with histone H1, including phase separation and phosphorylation fluctuations throughout the cell cycle. Furthermore, we discovered that the lysine-rich domain of Hho1 is buried by its second globular domain at the C-terminus, resulting in the loss of function that is similar to histone H1. Our study provides compelling evidence to suggest that Hmo1 shares linker histone H1 function in budding yeast and contributes to our understanding of the evolution of linker histone H1 across eukaryotes.

RNase H1 facilitates recombinase recruitment by degrading DNA-RNA hybrids during meiosis.

DNA-RNA hybrids play various roles in many physiological progresses, but how this chromatin structure is dynamically regulated during spermatogenesis remains largely unknown. Here, we show that germ cell-specific knockout of Rnaseh1, a specialized enzyme that degrades the RNA within DNA-RNA hybrids, impairs spermatogenesis and causes male infertility. Notably, Rnaseh1 knockout results in incomplete DNA repair and meiotic prophase I arrest. These defects arise from the altered RAD51 and DMC1 recruitment in zygotene spermatocytes. Furthermore, single-molecule experiments show that RNase H1 promotes recombinase recruitment to DNA by degrading RNA within DNA-RNA hybrids and allows nucleoprotein filaments formation. Overall, we uncover a function of RNase H1 in meiotic recombination, during which it processes DNA-RNA hybrids and facilitates recombinase recruitment.

Existence of sign-changing solutions for a gauged nonlinear Schrödinger equation with a quintic term

In this paper, we study the existence and asymptotic behavior of sign-changing solutions with arbitrary number of nodes to the following gauged nonlinear Schrödinger equation(0.1){−Δu+ωu+((hu(|x|))2|x|2+∫|x|+∞hu(s)su2(s)ds)u=λ|u|4uin R2,u∈H1(R2), where ω,λ>0 and hu(s)=12∫0sru2(r)dr is the so-called Chern-Simons term. The nonlocal term g(u):=((hu(|x|))2|x|2+∫|x|+∞hu(s)su2(s)ds)u is quintic in the sense that g(tu)=t5g(u), which is in complicated competition with the nonlinear term λ|u|4u. This causes that not all functions in H1(R2) can be projected onto the usual Nehari manifold, and so the classical Nehari manifold method is not applicable. By taking advantage of the Miranda theorem and Gersgorin disc theorem, via the variational method and gluing approach, we prove that for each positive integer k, the problem (0.1) admits a radial sign-changing solution Uk,6λ that changes sign exactly k times. Moreover, its energy is strictly increasing in k, and for any sequence {λn} with λn→+∞, up to a subsequence, λn14Uk,6λn converges to some U¯k,60∈H1(R2) which is a radial sign-changing solution with exactly k nodes to the following local equation{−Δu+ωu=|u|4uin R2,u∈H1(R2). Our results extend the existing ones of [6] from the super-quintic case to the quintic case.

Histone H1 regulates non-coding RNA turnover on chromatin in a m6A-dependent manner.

SummaryLinker histones are highly abundant chromatin-associated proteins with well-established structural roles in chromatin and as general transcriptional repressors. In addition, it has been long proposed that histone H1 exerts context-specific effects on gene expression. Here, we identify a function of histone H1 in chromatin structure and transcription using a range of genomic approaches. In the absence of histone H1, there is an increase in the transcription of non-coding RNAs, together with reduced levels of m6A modification leading to their accumulation on chromatin and causing replication-transcription conflicts. This strongly suggests that histone H1 prevents non-coding RNA transcription and regulates non-coding transcript turnover on chromatin. Accordingly, altering the m6A RNA methylation pathway rescues the replicative phenotype of H1 loss. This work unveils unexpected regulatory roles of histone H1 on non-coding RNA turnover and m6A deposition, highlighting the intimate relationship between chromatin conformation, RNA metabolism, and DNA replication to maintain genome performance.

Generalized Persistence of Entropy Weak Solutions for System of Hyperbolic Conservation Laws

Let u(t, x) be the solution to the Cauchy problem of a scalar conservation law in one space dimension. It is well known that even for smooth initial data the solution can become discontinuous in finite time and global entropy weak solution can best lie in the space of bounded total variations. It is impossible that the solutions belong to, for example, H1 because by Sobolev embedding theorem H1 functions are Hölder continuous. However, the author notes that from any point (t, x), he can draw a generalized characteristic downward which meets the initial axis at y = α(t, x). If he regards u as a function of (t, y), it indeed belongs to H1 as a function of y if the initial data belongs to H1. He may call this generalized persistence (of high regularity) of the entropy weak solutions. The main purpose of this paper is to prove some kinds of generalized persistence (of high regularity) for the scalar and 2 × 2 Temple system of hyperbolic conservation laws in one space dimension.

Multiple nodal solutions of the Kirchhoff-type problem with a cubic term

Abstract In this article, we are interested in the following Kirchhoff-type problem (0.1) − a + b ∫ R N ∣ ∇ u ∣ 2 d x Δ u + V ( ∣ x ∣ ) u = ∣ u ∣ 2 u in R N , u ∈ H 1 ( R N ) , \left\{\begin{array}{l}-\left(a+b\mathop{\displaystyle \int }\limits_{{{\mathbb{R}}}^{N}}| \nabla u\hspace{-0.25em}{| }^{2}{\rm{d}}x\right)\Delta u+V\left(| x| )u=| u\hspace{-0.25em}{| }^{2}u\hspace{1.0em}{\rm{in}}\hspace{0.33em}{{\mathbb{R}}}^{N},\\ u\in {H}^{1}\left({{\mathbb{R}}}^{N}),\end{array}\right. where a , b > 0 , N = 2 a,b\gt 0,N=2 or 3, the potential function V V is radial and bounded from below by a positive number. Because the nonlocal b ∣ ∇ u ∣ L 2 ( R N ) 2 Δ u b| \nabla u\hspace{-0.25em}{| }_{{L}^{2}\left({{\mathbb{R}}}^{N})}^{2}\Delta u is 3-homogeneous which is in complicated competition with the nonlinear term ∣ u ∣ 2 u | u\hspace{-0.25em}{| }^{2}u . This causes that not all function in H 1 ( R N ) {H}^{1}\left({{\mathbb{R}}}^{N}) can be projected on the Nehari manifold and thereby the classical Nehari manifold method does not work. By introducing the Gersgorin Disk theorem and the Miranda theorem, via a limit approach and subtle analysis, we prove that for each positive integer k k , equation (0.1) admits a radial nodal solution U k , 4 b {U}_{k,4}^{b} having exactly k k nodes. Moreover, we show that the energy of U k , 4 b {U}_{k,4}^{b} is strictly increasing in k k and for any sequence { b n } \left\{{b}_{n}\right\} with b n → 0 + , {b}_{n}\to {0}_{+}, up to a subsequence, U k , 4 b n {U}_{k,4}^{{b}_{n}} converges to U k , 4 0 {U}_{k,4}^{0} in H 1 ( R N ) {H}^{1}\left({{\mathbb{R}}}^{N}) , which is a radial nodal solution with exactly k k nodes of the classical Schrödinger equation − a Δ u + V ( ∣ x ∣ ) u = ∣ u ∣ 2 u in R N , u ∈ H 1 ( R N ) . \left\{\begin{array}{l}-a\Delta u+V\left(| x| )u=| u\hspace{-0.25em}{| }^{2}u\hspace{1.0em}{\rm{in}}\hspace{0.33em}{{\mathbb{R}}}^{N},\\ u\in {H}^{1}\left({{\mathbb{R}}}^{N}).\end{array}\right. Our results extend the existence result from the super-cubic case to the cubic case.

Single-stranded nucleic acid sensing and coacervation by linker histone H1

The linker histone H1 family is the most abundant group of eukaryotic chromatin-binding proteins, in which H1 is known for its role as a nucleosome compactor and an essential component of higher order chromatin structure. However, the mechanism underlying the diverse physiological functions of H1 remains unclear. Here we used single-molecule fluorescence and force microscopy to observe the behavior of H1 on DNA under different tensions in real time. Unexpectedly, we observed that H1 preferentially coalesces around nascent single-stranded DNA, forming condensate-like complexes.

Effect of Ions and Sequence Variants on the Antagonist Binding Properties of the Histamine H1 Receptor.

The histamine H1 receptor (H1R) is a G protein-coupled receptor (GPCR) and represents a main target in the treatment of allergic reactions as well as inflammatory reactions and depressions. Although the overall effect of antagonists on H1 function has been extensively investigated, rather little is known about the potential modulatory effect of ions or sequence variants on antagonist binding. We investigated the dynamics of a phosphate ion present in the crystal structure and of a sodium ion, for which we determined the position in the allosteric pocket by metadynamics simulations. Both types of ions exhibit significant dynamics within their binding site; however, some key contacts remain stable over the simulation time, which might be exploited to develop more potent drugs targeting these sites. The dynamics of the ions is almost unaffected by the presence or absence of doxepin, as also reflected in their small effect (less than 1 kcal·mol−1) on doxepin binding affinity. We also examined the effect of four H1R sequence variants observed in the human population on doxepin binding. These variants cause a reduction in doxepin affinity of up to 2.5 kcal·mol−1, indicating that personalized medical treatments that take into account individual mutation patterns could increase precision in the dosage of GPCR-targeting drugs.

Adjoint based optimal control of nonlocal advection with bilinear mixed constraints in H1

AbstractIn district heating, it is often required to control the system in such a way, that temperature and supply power are simultaneously bounded [1], which results in a set of box constraints for the control variable, and mixed bilinear state‐control‐constraint. The latter one is relaxed using a Moreau‐Yosida penalty approach, leading to a parametrized series of optimization problem, whereas the former one is handled by projection. This problem is studied at the example simplified one‐pipeline model, and numerically solved using a projected gradient algorithm. Due to the regularity required by the nonlocal boundary condition, the control variable has to be a function in H1 , such that the gradient computation and projection steps require an additional elliptic subproblem, which has to be solved.

Support of solutions of the linear Klein-Gordon equation and exact boundary controllability in non-cylindrical domains

This paper address to show that it is possible to extend each pair of functions of H1(Ω)×L2(Ω) to H1(R2)×L2(R2), with Ω⊂R2, with Ω⊂R2, such that the solution of the Cauchy problem for linear Klein-Gordon equation, with such extended initial data, vanishes in certain conical region of R2×[0,∞). After, we show how use it for obtain exact boundary control on certain non-cylindrical domains for above considered equation. The control time is obtained in any time greater then the value of the diameter of the domain on which the initial data is taken. The control is square integrable and acts on whole boundary of the non-cylindrical domain and it is given by conormal derivative associated to linear Klein-Gordon operator.

Mutations of the histone linker H1-4 in neurodevelopmental disorders and functional characterization of neurons expressing C-terminus frameshift mutant H1.4.

Rahman syndrome (RMNS) is a rare genetic disorder characterized by mild to severe intellectual disability, hypotonia, anxiety, autism spectrum disorder, vision problems, bone abnormalities and dysmorphic facies. RMNS is caused by de novo heterozygous mutations in the histone linker gene H1-4; however, mechanisms underlying impaired neurodevelopment in RMNS are not understood. All reported mutations associated with RMNS in H1-4 are small insertions or deletions that create a shared frameshift, resulting in a H1.4 protein that is both truncated and possessing an abnormal C-terminus frameshifted tail (H1.4 CFT). To expand understanding of mutations and phenotypes associated with mutant H1-4, we identified new variants at both the C- and N-terminus of H1.4. The clinical features of mutations identified at the C-terminus are consistent with other reports and strengthen the support of pathogenicity of H1.4 CFT. To understand how H1.4 CFT may disrupt brain function, we exogenously expressed wild-type or H1.4 CFT protein in rat hippocampal neurons and assessed neuronal structure and function. Genome-wide transcriptome analysis revealed ~ 400 genes altered in the presence of H1.4 CFT. Neuronal genes downregulated by H1.4 CFT were enriched for functional categories involved in synaptic communication and neuropeptide signaling. Neurons expressing H1.4 CFT also showed reduced neuronal activity on multielectrode arrays. These data are the first to characterize the transcriptional and functional consequence of H1.4 CFT in neurons. Our data provide insight into causes of neurodevelopmental impairments associated with frameshift mutations in the C-terminus of H1.4 and highlight the need for future studies on the function of histone H1.4 in neurons.

Regulation of the Development in Physcomitrium (Physcomitrella) patens implicates the functional differentiation of plant RNase H1s

R-loops, consisting of a DNA:RNA hybrid and a single-stranded DNA (ssDNA), form naturally as functional chromosome structures and are crucial in many vital biological processes. However, disrupted R-loop homeostasis will threat to the integrity and stability of genome. As the endonuclease, RNase H1 can efficiently recognize and remove excess R-loops to protect organisms from DNA damage induced by R-loop over-accumulation. Here, we investigated the function of RNase H1 in Physcomitrium (Physcomitrella) patens to illustrate its important role in the evolution of plants. We found that PpRNH1A dysfunction seriously affected shoot growth and branch formation in P. patens, revealing a noticeable functional difference between PpRNH1A and AtRNH1A of Arabidopsis. Furthermore, auxin signaling was significantly affected at the transcriptional level in PpRNH1A mutant plants, as a result of the accumulation of R-loops at several auxin-related genes. This study provides evidence that PpRNH1A regulates the development of P. patens by controlling R-loop formation at specific loci to modulate the transcription of auxin-related genes. It also highlights the interspecific functional differences between early land plants and vascular plants, despite crucial and conserved role of RNase H1 played in maintaining R-loop homeostasis.

Interactome of Site-Specifically Acetylated Linker Histone H1.

Linker histone H1 plays a key role in chromatin organization and maintenance, yet our knowledge of the regulation of H1 functions by post-translational modifications is rather limited. In this study, we report on the generation of site-specifically mono- and di-acetylated linker histone H1.2 by genetic code expansion. We used these modified histones to identify and characterize the acetylation-dependent cellular interactome of H1.2 by affinity purification mass spectrometry and show that site-specific acetylation results in overlapping but distinct groups of interacting partners. Among these, we find multiple translational initiation factors and transcriptional regulators such as the NAD+-dependent deacetylase SIRT1, which we demonstrate to act on acetylated H1.2. Taken together, our data suggest that site-specific acetylation of H1.2 plays a role in modulating protein-protein interactions.

Generalized Prager–Synge identity and robust equilibrated error estimators for discontinuous elements

The well-known Prager–Synge identity is valid in H1(Ω) and serves as a foundation for developing equilibrated a posteriori error estimators for continuous elements. In this paper, we introduce a new identity, that may be regarded as a generalization of the Prager–Synge identity, to be valid for piecewiseH1(Ω) functions for diffusion problems.For nonconforming finite element approximation of arbitrary odd order, we improve the current methods by proposing a fully explicit approach that recovers an equilibrated flux in H(div;Ø) through a local element-wise scheme. The local efficiency for the recovered flux is robust with respect to the diffusion coefficient jump regardless of its distribution.For discontinuous elements, we note that the typical approach of recovering a H1 function for the nonconforming error can be proved robust only under some restrictive assumptions. To promote the unconditional robustness of the error estimator with respect to the diffusion coefficient jump, we propose to recover a gradient in H(curl;Ω) space through a simple explicit averaging technique over facets. Our resulting error estimator is proved to be globally reliable and locally efficient regardless of the coefficient distribution. Nevertheless, the reliability constant is no longer to be 1.

Onto interpolation for the Dirichlet space and for [formula omitted

We give a characterization of onto interpolating sequences with finite associated measure for the Dirichlet space in terms of condenser capacity. In the Sobolev space H1(D) we define a natural notion of onto interpolation and we prove that the same condenser capacity condition characterizes all onto interpolating sequences. As a result, for sequences with finite associated measure, the problem of interpolation by an analytic function reduces to a problem of interpolation by a function in H1(D).

Some endpoint estimates for bilinear Coifman-Meyer multipliers

In this paper we establish mapping properties of bilinear Coifman-Meyer multipliers acting on the product spaces H1(Rn)×bmo(Rn) and Lp(Rn)×bmo(Rn), with 1<p<∞. As application of these results, we obtain some related Kato-Ponce-type inequalities involving the endpoint space bmo(Rn), and we also study the pointwise product of a function in bmo(Rn) with functions in H1(Rn), h1(Rn) and Lp(Rn), with 1<p<∞.

Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture.

Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction1, although their biological functions are poorly understood. Histone H1 (HIST1H1B-E) mutations are highly recurrent in B-cell lymphomas, but their cancer relevance and mechanism are unknown. Here we show that lymphoma-associated H1 alleles are genetic driver mutations in lymphomas. Disruption of H1 function results in profound architectural remodeling of the genome characterized by large-scale, yet focal shifts of chromatin from a compacted, to a relaxed state. This decompaction drives distinct changes in epigenetic states, primarily due to gain of histone H3 lysine 36 dimethylation, and/or loss of repressive H3 lysine 27 trimethylation. These changes unlock expression of stem cell genes that are normally silenced during early development. Loss of H1c and H1e alleles in mice conferred enhanced fitness and self-renewal properties to germinal center B-cells, ultimately leading to aggressive lymphoma with enhanced repopulating potential. Collectively, our data indicate that H1 proteins are normally required to sequester early developmental genes into architecturally inaccessible genomic compartments. We furthermore establish H1 as a bona fide tumor suppressor, whose mutation drives malignant transformation primarily through three-dimensional genome reorganization, followed by epigenetic reprogramming and derepression of developmentally silenced genes.

Variable slip window technology in transition detection on pitching airfoil

In the pitching motion, the unsteady transition and relaminarization position plays an important role in the dynamic characteristics of the airfoil. In order to facilitate the computer to automatically and accurately calculate the position of the transition and relaminarization, a Variable Slip Window Technology (VSWT) suitable for airfoil dynamic data processing was developed using the S809 airfoil experimental data in this paper and two calculation strategies, i.e., global strategy and single point strategy, were proposed: global strategy and single point strategy. The core of the VSWT is the selection of the window function h and the parameters setting in the h function. The effect of the VSWT was evaluated using the dimensionless pulse strength value (INB), which can be used to evaluate the signal characteristics, of the root mean square (RMS) value of the fluctuating pressure. It is found that: the h function characteristics have a significant influence on the VSWT. The suitable functions are Hn function constructed in this paper and step function. For the left boundary of the magnified area, the step function can obtain the largest INB value, but the robustness is not good. The H1 function (Gaussian-like function, n = 1) can show higher robustness while ensuring a large INB value. The two computing strategies, which are single point strategy and global strategy, have their own advantages and disadvantages. The former strategy, that is the single point strategy, can achieve a higher INB value, but the RMS magnification at the feature position needs to be known in advance. Although the INB value obtained by the latter strategy, that is the global strategy, is slightly smaller than the calculation results of the former strategy, it is not necessary to know the RMS magnification at the feature position in advance. So the global strategy has better robustness. The experimental data of NACA0012 airfoil was used to further validate the developed VSWT in this paper, and the results show that the VSWT developed in this paper can still double the INB value of the transition/relaminarization position. The VSWT developed in this paper has certain practicability, which is convenient for the computer to automatically determine the transition/relaminarization characteristics.