A National Cancer Institute-designated Comprehensive Cancer Center

Make an appointment: 800-826-HOPE
Singer-Sam, Judith, Ph.D. Laboratory Bookmark and Share

Laboratory of Judith Singer-Sam, Ph.D.

For a growing number of genes, only one of the two chromosomal copies (or alleles) is expressed, a phenomenon termed monoallelic expression. In some cases, there is random selection of the expressed allele; in others parental origin determines which allele is expressed, which is termed imprinting. Disorders with a genetic component in which either random monoallelic expression or imprinting may play a role include schizophrenia, multiple sclerosis, and diabetes.
 
Our goal is to understand the mechanism and extent of imprinting and monoallelic expression, and their possible relevance to inherited disorders, particularly those of the central nervous system. Towards this goal, we are studying a mouse locus corresponding to a human inherited mental retardation disorder known to involve imprinted genes, the Prader-Willi/Angelman Syndrome. We are also developing an assay that would make use of state-of-the-art microarray technology to probe for imprinting and monoallelic expression in the entire genome.
 

Judith Singer-Sam, Ph.D. Research

Monoallelic Expression in the Central Nervous System
Although most genes in a cell are expressed from both the maternal and paternal chromosome, there are exceptions. For example, in women, most X-linked genes are expressed from only one of the two X chromosomes, a phenomenon called X inactivation. In addition, there is a class of autosomal genes, termed imprinted genes, for which parental origin determines which allele is expressed. Finally, there are autosomal genes that appear at first glance to be bi-allelically expressed but actually show random monoallelic expression (sometimes termed allelic exclusion) at the single-cell level. These exceptions, examples of epigenetics, have proven to be of great interest for researchers because they shed light on gene regulation, chromatin structure, development, and the pattern of inheritance of certain genetic disorders.
 
My research program is focused on the potential role of allele-specific expression in development and function of the central nervous system (CNS). What is the evidence that genes likely to play a role in CNS function show such expression? Olfactory receptors, which are expressed in specialized cells of the CNS, show allelic exclusion, as does p120 catenin, which is involved in synapse formation. Intriguing recent work has shown that a number of factors involved in the immune response, including the genes for interleukin-2 and interleukin-4, also show allelic exclusion. Some of these genes are expressed in the CNS, and the possibility arises that other inflammation-sensitive genes in the CNS may show a similar pattern of expression.  Using gene expression profiling, we discovered that, Cdkn1a, coding for the cell cycle regulator p21Waf1/Cip1, is inflammation-sensitive in the CNS as well as other tissues.  While this gene is bi-allelically expressed, we expect to find additional immune response genes that do undergo monoallelic expression.
 
We have also developed an imprinting screen using expression microarrays. As a model system, we analyzed mice with imprinting defects in proximal chromosome 7; part of this region is analogous to human chromosome 15q11-q13, a locus associated with a number of behavioral and cognitive disorders including the well-studied Prader-Willi/Angelman Syndrome (PW/AS). Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the mouse PW/AS locus, in a region highly enriched in LINE-1 elements; the function of these transcripts is still unknown.  In separate work, we discovered, in collaboration with Dr. Chauncey Bowers (Department of Neurosciences) that the dense LINE-1 elements in this region are organized in a uniquely asymmetric way, perhaps related to imprinting at the locus.
 
Our current work involves the identification and characterization of genes that are subject to random monoallelic expression in the CNS. We have developed a microarray-based assay for genes that are both silenced and active at the same locus as evidenced by a dual DNA methylation pattern.  We further analyze candidate genes using SNP differences in cDNA of clonal neural stem cell lines derived from F1 hybrids of two different strains of mice. We have found a number of “hits” and are currently characterizing those that appear potentially most relevant to disorders of the CNS.
 

Singer-Sam, Judith, Ph.D. Laboratory

Laboratory of Judith Singer-Sam, Ph.D.

For a growing number of genes, only one of the two chromosomal copies (or alleles) is expressed, a phenomenon termed monoallelic expression. In some cases, there is random selection of the expressed allele; in others parental origin determines which allele is expressed, which is termed imprinting. Disorders with a genetic component in which either random monoallelic expression or imprinting may play a role include schizophrenia, multiple sclerosis, and diabetes.
 
Our goal is to understand the mechanism and extent of imprinting and monoallelic expression, and their possible relevance to inherited disorders, particularly those of the central nervous system. Towards this goal, we are studying a mouse locus corresponding to a human inherited mental retardation disorder known to involve imprinted genes, the Prader-Willi/Angelman Syndrome. We are also developing an assay that would make use of state-of-the-art microarray technology to probe for imprinting and monoallelic expression in the entire genome.
 

Research

Judith Singer-Sam, Ph.D. Research

Monoallelic Expression in the Central Nervous System
Although most genes in a cell are expressed from both the maternal and paternal chromosome, there are exceptions. For example, in women, most X-linked genes are expressed from only one of the two X chromosomes, a phenomenon called X inactivation. In addition, there is a class of autosomal genes, termed imprinted genes, for which parental origin determines which allele is expressed. Finally, there are autosomal genes that appear at first glance to be bi-allelically expressed but actually show random monoallelic expression (sometimes termed allelic exclusion) at the single-cell level. These exceptions, examples of epigenetics, have proven to be of great interest for researchers because they shed light on gene regulation, chromatin structure, development, and the pattern of inheritance of certain genetic disorders.
 
My research program is focused on the potential role of allele-specific expression in development and function of the central nervous system (CNS). What is the evidence that genes likely to play a role in CNS function show such expression? Olfactory receptors, which are expressed in specialized cells of the CNS, show allelic exclusion, as does p120 catenin, which is involved in synapse formation. Intriguing recent work has shown that a number of factors involved in the immune response, including the genes for interleukin-2 and interleukin-4, also show allelic exclusion. Some of these genes are expressed in the CNS, and the possibility arises that other inflammation-sensitive genes in the CNS may show a similar pattern of expression.  Using gene expression profiling, we discovered that, Cdkn1a, coding for the cell cycle regulator p21Waf1/Cip1, is inflammation-sensitive in the CNS as well as other tissues.  While this gene is bi-allelically expressed, we expect to find additional immune response genes that do undergo monoallelic expression.
 
We have also developed an imprinting screen using expression microarrays. As a model system, we analyzed mice with imprinting defects in proximal chromosome 7; part of this region is analogous to human chromosome 15q11-q13, a locus associated with a number of behavioral and cognitive disorders including the well-studied Prader-Willi/Angelman Syndrome (PW/AS). Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the mouse PW/AS locus, in a region highly enriched in LINE-1 elements; the function of these transcripts is still unknown.  In separate work, we discovered, in collaboration with Dr. Chauncey Bowers (Department of Neurosciences) that the dense LINE-1 elements in this region are organized in a uniquely asymmetric way, perhaps related to imprinting at the locus.
 
Our current work involves the identification and characterization of genes that are subject to random monoallelic expression in the CNS. We have developed a microarray-based assay for genes that are both silenced and active at the same locus as evidenced by a dual DNA methylation pattern.  We further analyze candidate genes using SNP differences in cDNA of clonal neural stem cell lines derived from F1 hybrids of two different strains of mice. We have found a number of “hits” and are currently characterizing those that appear potentially most relevant to disorders of the CNS.
 
Our Scientists

Our research laboratories are led by the best and brightest minds in scientific research.
 

Beckman Research Institute of City of Hope is internationally  recognized for its innovative biomedical research.
City of Hope is one of only 41 Comprehensive Cancer Centers in the country, the highest designation awarded by the National Cancer Institute to institutions that lead the way in cancer research, treatment, prevention and professional education.
Learn more about City of Hope's institutional distinctions, breakthrough innovations and collaborations.
Develop new therapies, diagnostics and preventions in the fight against cancer and other life-threatening diseases.
 
Support Our Research
By giving to City of Hope, you support breakthrough discoveries in laboratory research that translate into lifesaving treatments for patients with cancer and other serious diseases.
 
 
 
 


NEWS & UPDATES
  • Valentine’s Day is synonymous with dinner reservations, red roses, heart-shaped boxes of chocolates and — more often than not — unrealistically high expectations. Managing those expectations is great advice for all couples on Feb. 14 — and is especially important for couples confronting a cancer diagnosis. Focu...
  • With measles, what starts at a theme park in California definitely doesn’t stay at a theme park in California. Since the beginning of the current measles outbreak – traced to an initial exposure at Disneyland or Disney California Adventure during December – more than 100 people have been diagnosed with a diseas...
  • Even the most loving and secure relationship can be rattled by a life-threatening illness. When a woman is diagnosed with breast cancer, research shows one of the most important factors in helping her cope is having a supportive partner. But that partner can struggle with knowing what to say or how to best supp...
  • It’s been more than a century since Nobel Laureate Paul Ehrlich popularized the idea of a “magic bullet” targeting disease. Cancer researchers ever since have remained in hot pursuit of targeted therapies that home in on cancer cells while leaving normal cells unaffected. Linda Malkas, Ph.D., associate chair of...
  • Cancer patients face a daunting journey marked by challenges and uncertainties. For those undergoing bone marrow, or stem cell, transplantation, one complication poses a particular threat — chronic graft-versus-host disease (GVHD). Now, one researcher may have found a better way to control that threat. GVHD res...
  • Michele Dahlstein, a 50-year-old breast cancer survivor from Upland, California, celebrated her last day of chemotherapy on Dec. 30. She shares her story in her own words: I was diagnosed with breast cancer (invasive ductal carcinoma stage 2) on Aug. 11, 2014, after my yearly mammogram at City of Hope’s W...
  • The treatment of urologic cancers, including bladder cancer, is rapidly evolving. Here, urologic oncologic surgeon and kidney stone specialist Donald Hannoun, M.D., an assistant clinical professor in the Division of Urology and Urologic Oncology at City of Hope | Antelope Valley, explains the changes in hi...
  • A woman confronting metastatic breast cancer faces challenges that, at the outset, seem overwhelming. Research tells us these patients are especially vulnerable to anxiety, depression, hopelessness and other sources of distress. At the same time, they are asked to make complicated choices about their medical ca...
  • California health officials are opting to be safe rather than sorry when it comes to e-cigarettes. The increasingly popular devices are a public health threat, according to a California Department of Health report released Jan. 28. The department is seeking statewide regulation of e-cigarettes, saying they  emi...
  • “Not beyond us.” On World Cancer Day, researchers and caregivers around the globe are embracing this refrain. Specifically, the day calls for action to support healthier lifestyles, early cancer detection, quality of life and access to care. In a time of impressive scientific discovery and narrowing...
  • With more advanced cancer treatments and therapies saving lives every day, it’s safe to say cancer is “Not beyond us,” the official tagline for this year’s World Cancer Day. This year’s World Cancer Day observance takes place on Wednesday, Feb. 4, and focuses on cancer prevention, detection an...
  • Does our environment increase our risk of cancer? What about plastic bottles, radiation, chemicals, soy products …? Do they cause cancer? With so many cancer fears, rumors and downright urban legends circulating among our friends and colleagues, not to mention in the media and blogosphere, why not ask the...
  • With this week’s World Cancer Day challenging us to think about cancer on a global scale, we should also keep in mind that daily choices affect cancer risk on an individual scale. Simply put, lifestyle changes and everyday actions can reduce your cancer risk and perhaps prevent some cancers. According to ...
  • If you haven’t heard the term “precision medicine,” you will. If you don’t have an opinion about access to it, you will. On Friday, President Barack Obama unveiled details of the Precision Medicine Initiative, an effort intended to accelerate cancer research in a powerful way, giving doctors new knowledge and n...
  • The lack of a practical way to produce and store enough stem cells for larger-scale therapies and clinical trials is creating a bottleneck in stem cell research. A new grant to City of Hope from the California Institute for Regenerative Medicine (CIRM) will help solve that problem. The $899,728 grant, awarded T...