#prc2

[whats-in-a-sentence]

A model showing how DNA demethylation, DNA methylation, and FIS-PRC2-mediated histone methylation may regulate MEG expression in the endosperm is shown in Figure 21.27.

"Plant Physiology and Development" int'l 6e - Taiz, L., Zeiger, E., Møller, I.M., Murphy, A.

[covenawhite66]

The same DNA is used in cells across the body but each type of cell has different functions. The different functions are from using different areas of a DNA strand to activate a specific gene.

Genetic loops regulate which genes are repressed in a cell not to be activated.

PRC1 and PRC2 are regulators that prevent developmental genes from becoming activated at the wrong time or in the wrong cell.

This was tested on a mouse embryo. A gene that affects cohesion was experimented with.

[tushar38]

EZH2 Inhibitors: Promising Results in Lymphoma Treatment

EZH2 inhibitors represent a significant advancement in the field of cancer therapy, targeting a crucial component of the epigenetic machinery involved in gene regulation. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that plays a pivotal role in the Polycomb repressive complex 2 (PRC2), which regulates gene expression by modifying chromatin structure. Dysregulation of EZH2 has been implicated in the development and progression of various cancers, making it a promising target for therapeutic intervention.

The mechanism of action of EZH2 inhibitors involves blocking the enzyme's ability to methylate histone proteins, thereby preventing the repression of tumor suppressor genes. This reactivation of tumor suppressor genes can inhibit cancer cell growth and proliferation, induce apoptosis, and enhance the immune response against tumors. The therapeutic potential of EZH2 inhibitors has been demonstrated in several preclinical and clinical studies, particularly in cancers such as lymphoma, sarcoma, and certain solid tumors.

One of the most notable successes of EZH2 inhibitors is in the treatment of relapsed or refractory follicular lymphoma and diffuse large B-cell lymphoma (DLBCL). Tazemetostat, the first FDA-approved EZH2 inhibitor, has shown significant clinical activity in patients with EZH2-mutant follicular lymphoma, providing a new treatment option for this patient population. This approval has spurred further research into the broader applications of EZH2 inhibitors across various cancer types.

Beyond lymphomas, EZH2 inhibitors are being explored in combination with other cancer therapies to enhance their efficacy. Combining EZH2 inhibitors with immune checkpoint inhibitors, for instance, is a promising strategy to overcome resistance mechanisms and improve anti-tumor responses. Additionally, ongoing research is investigating the role of EZH2 in other diseases, including certain neurological disorders and developmental syndromes, expanding the potential therapeutic applications of these inhibitors.

Despite their promise, the development and clinical use of EZH2 inhibitors face several challenges. Resistance to EZH2 inhibitors can develop, necessitating the identification of biomarkers to predict which patients are most likely to benefit from these treatments. Additionally, understanding the long-term effects and potential toxicities associated with EZH2 inhibition is crucial for optimizing their clinical use.

In conclusion, EZH2 inhibitors are a groundbreaking development in cancer therapy, offering hope for patients with difficult-to-treat cancers. By targeting a key epigenetic regulator, these inhibitors have the potential to significantly impact cancer treatment paradigms. As research progresses, the full therapeutic potential of EZH2 inhibitors will continue to unfold, promising new avenues for combating cancer and possibly other diseases linked to epigenetic dysregulation.

[rnomics]

Tyrosine 1-phosphorylated #RNA polymerase II transcribes PROMPTs to facilitate proximal promoter pausing and induce global transcriptional repression in response to DNA damage [RESEARCH]

DNA damage triggers a complex transcriptional response that involves both activation and repression of gene expression. In this study, we investigated global changes in transcription in response to ionizing irradiation (IR), which induces double-strand breaks in DNA. We used mNET-seq to profile nascent transcripts bound to different phosphorylated forms of the #RNA polymerase II (#RNA Pol II) C-terminal domain (CTD). We found that IR leads to global transcriptional repression of protein-coding genes, accompanied by an increase in antisense transcripts near promoters, called PROMPTs, transcribed by #RNA Pol II phosphorylated on tyrosine 1 (Y1P) residue of the CTD. These Y1P-transcribed PROMPTs are enriched for PRC2 binding sites and associated with #RNA Pol II proximal promoter pausing. We show the interaction between Y1P #RNA Pol II and PRC2, as well as PRC2 binding to PROMPTs. Inhibition of PROMPTs or depletion of PRC2 leads to loss of transcriptional repression. Our results reveal a novel function of Y1P-dependent PROMPTs in mediating PRC2 recruitment to chromatin and #RNA Pol II promoter pausing in response to DNA damage. http://genome.cshlp.org/cgi/content/short/34/2/201?rss=1&utm_source=dlvr.it&utm_medium=tumblr

[pknoepfl]

OCT4-SOX DNA dance, PRC2, a noisy competition & more cell weekly reads

OCT4-SOX DNA dance, PRC2, a noisy competition & more cell weekly reads

What’s new in the stem cell, cell therapy, and regenerative medicine world as well as biomedical science more generally including cancer?

There’s quite a bit of news as reflected in media pieces and new pubs. Today’s post is focused on pubs that just came out.

For last week’s recommended reads see here.

Oct4-Sox2 Nucleosome Binding & Impact in mESCs

This is one of my favorite papers of 2020 so…

[symbiotic-science]

Plant scientists at the Universities of Birmingham and Nottingham have unravelled a mechanism that enables flowering plants to sense and 'remember' changes in their environment.

The research, published in the Journal Nature Communications, reveals potential new targets that could support the development of new plant varieties, including cereals and vegetables, that can adapt to different environmental conditions.

Plants' memory function enables them to accurately coordinate their development in response to stress or to the changing seasons. For example, many plants remember the extended cold of winter, which ensures that they only flower in spring when warmer temperatures return. One way they do this is through a group of proteins called the PRC2. In the cold these proteins come together as a complex and switch the plant into flowering mode. Little is known about how the PRC2 detects environmental change to make sure it is only active when needed.

This new study, which was carried out in collaboration with scientists from the Universities of Oxford and Utrecht, provides new insight into the 'environment sensing' function of the PRC2.

Researchers discovered that a core component of the complex—a protein called VRN2—is extremely unstable. In warmer temperatures and when oxygen is plentiful, VRN2 protein continually breaks down. When environmental conditions become more challenging, for example when a plant is flooded and oxygen is low, VRN2 becomes stable and enhances survival. VRN2 protein also accumulates in the cold. This allows the PRC2 complex to trigger flowering once temperatures rise. The team investigated the reasons for this and found a surprising similarity between plant responses to cold and low oxygen experienced during flooding.

"Plants have a remarkable ability to sense and remember changes in their environment, which allows them to control their life cycle," explains lead author Dr. Daniel Gibbs, from the School of Biosciences at the University of Birmingham. "VRN2 is continually being broken down when it is not needed, but accumulates under the right environmental conditions. In this way, VRN2 directly senses and responds to signals from the environment, and the PRC2 remains inactive until required."

[tumimmtxpapers]

Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic therapeutic viruses

Immune checkpoint blockade (ICB) has demonstrated clinical success in "inflamed" tumors with substantial T-cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the Polycomb-repressive complex 2 (PRC2) core components, EED or SUZ12, a prevalent genetic event in malignant peripheral nerve sheath tumor (MPNST)... http://dlvr.it/SV8t2w

[whats-in-a-sentence]

One common type of DNA modification is the methylation of cytosine residues (Figure 2.14A). (...) One, two, or three methyl groups can be added to a single lysine (Figure 2.14B). (...) The resulting gap between nucleosomes is now wide enough for RNA polymerase to bind and initiate transcription (Figure 2.14C). (...) The chromatin structure is then "remodeled" in an ATP-requiring reaction and subsequently methylated, resulting in tighter condensation and heterochromatization of the DNA region involved (see Figure 2.14). (...) Polychrome group protein complexes include multiple forms of Polycomb repressive complex 2 (PRC2), which catalyzes methylation of histones, which are components of nucleosomes whose methylation tends to inhibit transcription of the associated DNA (see Figure 2.14).

"Plant Physiology and Development" int'l 6e - Taiz, L., Zeiger, E., Møller, I.M., Murphy, A.

[covenawhite66]

"A carefully orchestrated regulatory machinery is required to ensure every cell in the body is expressing its correct gene set to exert its dedicated function.

PRC1- and PRC2-repressed genes come together, the genome forms loops. Loops are known to play a role in activating genes, but it has been more challenging to study how loops might help repress genes.

Developmental disorders and cancer happen when there are flaws in genome loops

Polycomb Repressive Complexes 1 and 2 (PRC1, PRC2)

Gene expression is primarily controlled by DNA binding transcription factors directing the transcriptional apparatus.

[rnomics]

The impact of SWI/SNF and NuRD inactivation on gene expression is tightly coupled with levels of #RNA polymerase II occupancy at promoters [RESEARCH]

SWI/SNF and NuRD are protein complexes that antagonistically regulate DNA accessibility. However, repression of their activities often leads to unanticipated changes in target gene expression (paradoxical), highlighting our incomplete understanding of their activities. Here we show that SWI/SNF and NuRD are in a tug-of-war to regulate PRC2 occupancy at lowly expressed and bivalent genes in mouse embryonic stem cells (mESCs). In contrast, at promoters of average or highly expressed genes, SWI/SNF and NuRD antagonistically modulate #RNA polymerase II (Pol II) release kinetics, arguably owing to accompanying alterations in H3.3 and H2A.Z levels at promoter-flanking nucleosomes, leading to paradoxical changes in gene expression. Owing to this mechanism, the relative activities of the two remodelers potentiate gene promoters toward Pol II–dependent open or PRC2-dependent closed chromatin states. Our results highlight #RNA Pol II occupancy as the key parameter in determining the direction of gene expression changes in response to SWI/SNF and NuRD inactivation at gene promoters in mESCs. http://genome.cshlp.org/cgi/content/short/33/3/332?rss=1&utm_source=dlvr.it&utm_medium=tumblr

[pknoepfl]

Sunday brunch buffet of stem cell good news, fun links, & cool papers

Sunday brunch buffet of stem cell good news, fun links, & cool papers

Enjoy! A brunch for the brain.

News and links

CBER Director Focuses on Flexibility to Advance Regenerative Medicines

Lab-Grown Blood Stem Cells Produced at Last

Transplanted stem cells become eggs in sterile mice

Liao, et al Figure 2D

Maryland fund awards $8.5 million for stem cell research

Positively good news from Asterias for CIRM-funded stem cell clinical trial for spinal cord injury

Sergio…

[sbgridconsortium]

Investigating complexes involved in epigenetic regulation

Polycomb repressive complex 2 (PRC2) is involved in the epigenetic regulation of gene expression which is critical during embryonic development and for the maintenance of cell type. Despite these important roles, it has remained unknown how cofactors, such as AEBP2 and JARID2 mechanistically regulate the activity of this complex. 

Based on the recognition of the monoubiquitination of histone H2A (H2AK119ub1) by PRC2, SBGrid member Eva Nogales and other researchers have been working to use cryo-EM and biochemical assays to investigate the roles of AEBP2 and JARID2 in PRC2′s activity and recognition of H2AK119ub1. The authors report a structure of PRC2 in complex with both cofactors AEBP2 and JARID2 bound to a nucleosome containing H2AK119ub1.

Above: Structure of PRC2 in complex with JARID2 and AEBP2 bound to Ncl-ub. CC BY SBGrid.

They not only found that the cofactors interact with a ubiquitin and the H2A-H2B interface, but they also determined that cofactors AEBP2 and JARID2 help to recruit and activate PRC2 through their recognition of H2AK119ub1. While JARID2 stimulates PRC2 through interactions with the EED of the polycomb protein and the H2AK119ub, AEBP2 plays an additional role as a scaffold. This work provides a mechanistic basis for AEBP2 and JARID2 regulation of PRC2 recognition and activity.

Read more about this research in Science.

[pinoywhealth]

Researchers have identified a molecular 'address' that explains how the cancer-related protein PRC2 binds to RNA to silence genes. The study resolves a longstanding debate about the contradictory behavior between PRC2 and RNA. The findings could have important implications for...

[huielanguageliteracy]

Module 10 Literacy Post

Observation Notes

*The tutoring and teaching section I observed focused on numerical mathematics problems rather than literacy development due to the specific room I was placed in as well as the day of the week on which I observed. Therefore, the following notes will refer to a mathematics lesson rather than a literacy lesson.

 1.      What do you notice about student behaviors?

a.      Students were given a number of math problems that correlated with problems they were solving in their own respective classrooms. Both students in the room were operating at a 6th grade level.

b.      Students did problems individually then worked with the tutor to double check their work and learn why their answers were either correct, incorrect, or partially correct.

c.      Students usually responded with simple answers that only identified their responses to each question. If the answers they provided were incorrect, students often would explain how they got that answer, or they would quickly review their work to see if they were able to identify their mistake(s) on their own.

d.      Students were working through a combination of problem types including: converting improper fractions to mixed fraction, reducing fractions, converting percentages to decimals, and converting percentages to fractions.

2.      How did the teachers address those behaviors?

a.      The teacher provided numerous opportunities for students to respond as well as checks for understanding that ensured that students not only knew the answers to each problem, but also how to get to the correct answer and why the method of answering the question worked for each problem.

b.      The teacher/ tutor demonstrated the problem on a virtual whiteboard while verbally explaining each step and allowing the student to answer each question or step rather than giving them the answers.

c.      The teacher re-iterated what each student said as they worked through the problem to make sure they understood each comment as well as helping to teach the other students who were watching the problems being solved.

d.      The teacher asked the students supplemental questions to draw out the student’s thinking and understanding. Again, this ensured that the students were reaching conclusions and answering the questions on their own rather than giving them the correct answers.

e.      The teacher made sure to review academic language as it appeared within each problem.

3.      Skills and Strategies Required for Comprehending Narrative Text

a.      Before Reading:

  i.     Predicting – Using the context of what has already been read to guess what will happen later in the story. “Predicting helps readers … begin to understand that reading is more than just reading words correctly.”

 ii.     Setting a Purpose – “After reading the title of a text, readers should ask themselves what genre the text belongs to.”

b.      During Reading:

i.       Making Inferences – Teacher should ask open-ended questions in order to aid students in this process.

ii.      Connecting prior knowledge to texts – “There are three types of background knowledge: literary background, world knowledge, and life experiences.”

iii.    Self-monitoring – “The ability of readers to figure out if something sounds right.”

iv.    Generating visual images – “Readers should visualize the scene so vividly that they can almost hear the surrounding noises and smell the scents.”

c.      After Reading:

  i.     Retelling story elements – “ The readers ability to name the main characters, state the problem, and relate events that lead to the climax and resolution.”

 ii.     Drawing conclusions – “Students who comprehend the stories draw conclusions based on textual clues or previous experiences.” – These conclusions usually answer the question “why?”

 iii.     Elaborating on the author’s intent – Why did the author make the choices they did? Why did the author choose to write this text? “Teach students to consider the author’s perspective as well as other perspectives by examining stories written from opposing points of view.”

4.      Skills and Strategies Required for Informational Texts:

a.      Text Structure – Informational texts are structured differently than a narrative text, so there are organizational patterns in informative texts that a reader should understand:

   i.     Description (enumeration) – to begin, first, secondly, next, etc.

  ii.     Time frame (chronology) – not long after, now, before, following, etc.

 iii.     Compare/ Contrast – however, but, as well as, on the other hand, etc.

 iv.     Cause/ Effect & Problem/ Solution – because, since, therefore, consequently, etc.

 v.     Persuasion/ Argument – consequently, specifically, next, finally, etc.

 vi.     Listing – “authors may merely list all of the things that fall into a particular category.”

 vii.     Classification/ Hierarchy – “to show relationships among concepts.”

b.      Prior Knowledge – “includes all of life’s experiences… that take students out of their immediate surroundings to help them develop a broader view of the world in which they live.”

c.      Technical Words & Word Choice – this includes “the academic and domain – specific vocabulary used in informational texts.” In order to comprehend this type of vocabulary, students will need context clues in order to understand the greater context that informs it.

d.      Diagrams and Graphics – these can help students comprehend the context of the text.

e.      Setting a Purpose – teachers should “pose a non-specific question that encourages students to comprehend the entire text.” Otherwise, students may skim the parts of the text that do not directly answer a more specifically posed question.

5.      5 Possible Activities to Support Comprehension:

a.      Partner Reading and Content Too (PRC2) – “two English learners collaborate on reading a text together. The teacher is the silent observer and cheerleader. First, the partners preview the book. Then, the partners read a two-page spread silently. Then each partner rereads his page again and writes two questions to ask [their] partner. The two students discuss the information and answer the questions.”

b.      Read – Aloud – “A teacher can show students how informational texts differ from narrative text and what strategies she uses to make sense of expository text.”

c.      Dramatizing informational texts – Have students act out a portion of a text through a skit, song, or dance. This is especially helpful for kinesthetic learners.

d.      Request – In this activity, the teacher and the students all read the same text. Then, the students ask question that could be answered through the text, and the teacher responds. These questions must be asked in a comprehensible way.

e.      Checklist – Students will read a text, and the teacher will provide pre-meditated statements about the text that could be answered with either yes or no. Then, after the student has identified the true and false statements, go back and re-word the false statements to make them true.

Resource/ Text: DeVries, B. A. (2004). Literacy assessment and intervention for the elementary classroom. Scottsdale, AZ: Holcomb Hathaway.

[nikhildev1810]

Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals

Epigenetic processes regulate gene expression by modulating the frequency, rate, or extent of gene expression in a mitotically or meiotically heritable way that does not entail a change in the DNA sequence. Originally the definition applied only to heritability across generations but later also encompassed the heritable changes that occur during cellular differentiation within one organism.

Molecular analysis shows epigenetic changes comprise covalent modifications, such as methylation and acetylation, to DNA and histones. RNA interference has been implicated in the initiation of some epigenetic changes, for example transcriptional silencing of transposons. Proteins which bind to the modified DNA and histones are then responsible for repressing transcription and for maintaining the epigenetic modifications during cell division.

Access Full PDF >>

During differentiation, patterns of gene expression are established by polycomb complexes PRC1 and PRC2. PRC2 methylates histones and DNA to produce the initial marks of repression: trimethylated lysine-27 on histone H3 (H3K27me3) and 5-methylcytosine in DNA. PRC2, through its component EZH2 or, in some complexes, EZH1 trimethylates lysine-27 of histone H3. The H3K27me3 produced by PRC2 is bound by the Polycomb subunit of PRC1. PRC1 ubiquitinates histone H2A and maintains repression.

PRC2 and other epigenetic systems modulate gene expression through DNA methyation, the transfer of a methyl group from S-adenosylmethionine to the 5 position of cytosine in DNA by a family of DNA methyltransferases (DNMTs): DNMT1, DNMT3A, and DNMT3B.

In the reverse process TET1,2,3 and TDG demethylate DNA through the oxidation of the methyl group of 5-methylcytosine by TET enzymes and the excision of the oxidized product (5-formylcytosine or 5- carboxylcytosine) by TDG.

Ribosomal RNA (rRNA) genes are activated and deactivated according to the metabolic requirements of the cell. Positive epigenetic regulation of rRNA expression occurs through chromatin modifications produced by activators such as ERCC6 (CSB), the B-WICH complex, and histone acetylases such as KAT2B (PCAF). Negative epigenetic regulation of rRNA expression occurs through chromatin modifications produced by repressors such as the eNoSC complex, SIRT1, and the NoRC complex.

I hope this article was helpful regarding Epigenetics? and I am sure you’ll have more questions.

Submit Your Question @ Here

Reference

theinsightpartners.com

reactome.org

[rnomics]

Targeting #RNA with small molecules: Lessons learned from Xist #RNA [Perspective]

Although more than 98% of the human genome is non-coding, nearly all drugs on the market target one of about 700 disease-related proteins. However, an increasing number of diseases are now being attributed to non-coding RNA and the ability to target them would vastly expand the chemical space for drug development. We recently devised a screening strategy based upon affinity-selection mass spectrometry and succeeded in identifying bioactive compounds for the non-coding RNA prototype, Xist. Once such compound, termed X1, has drug-like properties and binds specifically to the RepA motif of Xist in vitro and in vivo. Small-angle X-ray scattering analysis reveals that X1 changes the conformation of RepA in solution, thereby explaining the displacement of cognate interacting protein factors (PRC2 and SPEN) and inhibition of X-chromosome inactivation. In this perspective, we discuss lessons learned from these proof-of-concept experiments and suggest that RNA can be systematically targeted by drug-like compounds to disrupt RNA structure and function. http://rnajournal.cshlp.org/cgi/content/short/rna.079523.122v1?rss=1&utm_source=dlvr.it&utm_medium=tumblr